| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Physiological Reviews, Vol. 80, No. 4, October 2000, pp. 1337-1372
Copyright ©2000 by the American Physiological Society
Department of Physiology, Charles University Second Medical School, Prague, Czech Republic
I. INTRODUCTION
A. Pulmonary Hypertension
B. NO and NO Synthases
II. NITRIC OXIDE IN THE REGULATION OF THE BASAL TONE OF THE NORMAL PULMONARY VESSELS
A. Adults
B. Fetal and Neonatal Pulmonary Circulation
III. ROLE OF NITRIC OXIDE IN PULMONARY VASOCONSTRICTION
IV. NITRIC OXIDE SYNTHESIS IN CHRONIC PULMONARY HYPERTENSION
A. Effects of NOS Inhibitors
B. Measurements of NOS Activity
C. NOS Expression
D. Endothelium-Dependent Vasodilation
E. Interim Summary: Changes of NO Synthesis in Pulmonary Hypertension
V. REMODELING OF THE PULMONARY VASCULAR BED IN PULMONARY HYPERTENSION
A. Role of Injury to the Pulmonary Vascular Wall
B. Effects of NO on Radical Injury of Lung Vessels
C. Effects of NO on Remodeling of the Pulmonary Vascular Wall
VI. GENERAL SUMMARY AND CONCLUSIONS
 |
ABSTRACT |
|---|
 Top NextReferences
|
|---|
Hampl, Václav and
Jan Herget.
Role of Nitric Oxide in the Pathogenesis of Chronic
Pulmonary Hypertension. Physiol. Rev. 80: 1337-1372, 2000.
Chronic pulmonary hypertension is a
serious complication of a number of chronic lung and heart diseases. In
addition to vasoconstriction, its pathogenesis includes injury to the
peripheral pulmonary arteries leading to their structural remodeling.
Increased pulmonary vascular synthesis of an endogenous vasodilator,
nitric oxide (NO), opposes excessive increases of intravascular
pressure during acute pulmonary vasoconstriction and chronic pulmonary
hypertension, although evidence for reduced NO activity in pulmonary
hypertension has also been presented. NO can modulate the degree of
vascular injury and subsequent fibroproduction, which both underlie the
development of chronic pulmonary hypertension. On one hand, NO can
interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the
injury. On the other hand, NO may combine with oxygen radicals to yield
peroxynitrite and other related, highly reactive compounds. The
oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of
NO is determined by the relative amounts of NO and reactive oxygen
species. We speculate that this balance may be shifted toward more
severe injury especially during exacerbations of chronic diseases
associated with pulmonary hypertension. Targeting these adverse effects
of NO-derived radicals on vascular structure represents a potential
novel therapeutic approach to pulmonary hypertension in chronic lung diseases.
| |
I. INTRODUCTION |
|---|
|
TopPreviousNextReferences
|
|---|
Chronic injury to the pulmonary vasculature results in sustained pulmonary hypertension. Although various forms of pulmonary hypertension are a significant medical problem, mechanisms of development of this syndrome are unclear. Consequently, current options for effective prevention and therapy are limited.
One of the fastest growing areas of biomedical research during the last decade has been the biological role of endogenously produced nitric oxide (NO). Enormous evidence has accumulated showing an important role of this simple molecule in a wide variety of physiological functions, including regulation of vascular tone and mesenchymal cell growth.1 Lots of work has also been devoted to finding out the role played by NO in the normal and hypertensive pulmonary circulation. Reviewing the findings of that work is the objective of this article. The available data support the possibility that in pulmonary hypertension, endogenous NO can act not only to suppress the increase in vascular tone, but depending on conditions not yet well characterized, also to promote the vascular wall injury. The large, promising, and rapidly expanding area of the therapeutic manipulations of NO activity in pulmonary hypertension (inhaled NO gas, gene therapy) is not covered in this review; the interested reader is referred to recent reviews published elsewhere (54, 75, 121, 145, 164, 180, 194, 214).
A. Pulmonary Hypertension
As reviewed extensively elsewhere (295, 389), pulmonary hypertension is defined clinically as a condition of elevated pulmonary arterial pressure and/or pulmonary vascular resistance. It is a syndrome common to a variety of lung and heart diseases, such as chronic obstructive lung disease, lung fibrosis, adult respiratory distress syndrome, mitral stenosis, or congenital heart defects. Pulmonary hypertension also exists in a primary form, which is a relatively rare but serious disease (1, 66). Pulmonary hypertension secondary to pulmonary or cardiac diseases significantly worsens the prognosis of the primary disease (389).
Pulmonary hypertension presents an increased load to the right ventricle, which consequently hypertrophies and tends to fail. In fact, right heart failure is the most common cause of death in pulmonary hypertension (389).
The elevated vascular resistance in pulmonary hypertension is a result of an increase in vascular tone and of structural remodeling of the peripheral pulmonary arteries. The remodeling affects both vascular smooth muscle, which hypertrophies and proliferates, and vascular wall connective tissue, which increases in amount and undergoes qualitative changes. The endothelium is often affected as well. All of that reduces vascular lumen and thus increases vascular resistance to blood flow. It also makes the vascular wall less compliant. A relative pathogenetic significance of the functional and structural components varies with the type and stage of the disease. In the developed pulmonary hypertension, the importance of structural remodeling prevails (298), as suggested by the relative resistance of various types of pulmonary hypertension to vasodilator therapy (see Refs. 275, 276 for review).
Although chronic pulmonary hypertension is caused by a variety of pathogenetic factors, they all lead to vasoconstriction and structural remodeling of surprising uniformity. It suggests that at least part of the pathogenetic chain is similar despite the diverse origins of the disease. Injury to the pulmonary vascular wall and resulting reparatory processes are likely to be such a common phenomenon.
Various causes of chronic lung vascular injury were studied in different models of experimental pulmonary hypertension (for review see Refs. 139, 143, 296). Three major mechanisms (Fig. 1), namely vascular wall injury, abnormal shear stress of endothelial cells due to locally increased blood flow, and increase of transmural pressure across the vascular wall, interact in most cases of pulmonary hypertension, although their relative importance may differ.
|
As discussed in detail in recent reviews (17, 146, 290, 315, 324, 330, 353, 382, 389), a variety of intercellular and intracellular messenger molecules appear to be involved in the mechanism of pulmonary hypertension. However, their exact interplay is unclear, as is the primary stimulus to switch it on. Recent data point to alterations in the metabolism of vascular wall matrix proteins as a significant part of the mechanism of pulmonary hypertension (290). The extracellular matrix is an important denominator of mesenchymal cell migration, growth, and differentiation (331).
An important factor in the development of pulmonary hypertension is chronic or intermittent alveolar hypoxia. Lung tissue hypoxia accompanies most of the lung and heart diseases associated with pulmonary hypertension. It is not surprising, therefore, that exposure of animals to hypoxic environment has been the most often used experimental model of chronic pulmonary hypertension.
A distinction should be made between the effects of acute and chronic hypoxia. Acute hypoxia causes pulmonary vasoconstriction, which is one of the hallmarks of pulmonary vascular regulation. Systemic vessels generally respond to hypoxia with vasodilation or no change in tone. Hypoxic pulmonary vasoconstriction reduces blood flow to poorly ventilated areas of the lung in favor of the flow into the better ventilated regions. That helps to optimize lung ventilation/perfusion matching and consequently also the oxygenation of the blood. Hypoxic pulmonary vasoconstriction is a local lung regulatory mechanism. It is fast in onset (165) and is readily reversible upon reoxygenation.
Chronic hypoxia causes pulmonary hypertension, which often has a vasoconstriction component too. However, morphological remodeling of the pulmonary vascular wall appears to be more important than vasoconstriction (298).
B. NO and NO Synthases
NO is a simple molecule with one unpaired electron, i.e., it is a
free radical. In the presence of oxygen, NO undergoes oxidation, which
follows a second-order kinetics. Hence, when NO levels are high, it
is oxidized within seconds. On the other hand, when NO levels are
relatively low, as is often the case in vascular tissues (30, 167, 217), its
half-life can be hours or more. Oxidation end-product of NO is
nitrite (NO2
) in aqueous solutions and nitrate
(NO3) in the presence of oxyhemoglobins (e.g., in
blood) (157). NO and its oxidation products are often
collectively referred to as NOx. The biologically relevant
aspects of NO chemistry were recently reviewed in detail elsewhere
(15, 119, 156,
178).
NO is an important endogenous vasodilator produced by endothelial cells. It also serves as a neurotransmitter. High levels of NO and products of its interaction with oxygen free radicals are toxic, a fact which is utilized by cells of the immune system to kill invading bacteria or tumor cells.
NO is produced in mammalian cells by an oxygen-dependent, five-electron oxidation of a terminal guanidino nitrogen of L-arginine. Aside from NO, the reaction yields L-citrulline. The multistep reaction is catalyzed by a single heme-containing enzyme, NO synthase (NOS; EC 1.14.13.39), which exists in three isoforms. All isoforms are active as homodimers, are stereospecific (D-arginine is not a substrate), and require reduced nicotinamide adenine dinucleotide phosphate, 6(R)-5,6,7,8-tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide as cofactors. Isozyme I (subunit molecular mass ~160 kDa), encoded by a gene located on the human chromosome 12, is constitutively expressed in many central and peripheral neurons and is therefore often called neuronal NOS (nNOS). It can also be present in certain epithelial and vascular smooth muscle cells (including pulmonary) (340). Its activity is regulated by calcium-dependent binding of calmodulin. Type II NOS (~130 kDa; encoded by a gene on human chromosome 17) is inducible by a variety of factors related to inflammation and therefore is often referred to as inducible NOS (iNOS). It is regulated at the level of gene expression; once expressed, it produces NO at a high rate independently of the intracellular concentration of the free calcium ion ([Ca2+]i). The third isoform, NOS III or endothelial NOS (eNOS; ~133 kDa), is encoded by a gene on human chromosome 7. In most endothelial cells and several other cell types, it is expressed constitutively, but the rate of the eNOS gene transcription and translation can be modulated by numerous factors, such as the shear stress of the endothelial surface (reviewed in Ref. 94). The eNOS enzyme activity is regulated by calcium-dependent binding of calmodulin and by tyrosine phosphorylation (111). Although the initial research of the physiology of NO in the vasculature focused on the eNOS, recent data suggest that at certain situations the remaining two NOS isoforms may also contribute to the vascular regulation (36, 291). More detailed discussions of NOS enzymology are available elsewhere (92, 94, 95, 150, 243, 250, 356).
The target tissue effects of NO depend on its quantity. At high concentrations, NO readily reacts with oxygen and especially with superoxide, forming highly reactive, cytotoxic substances, such as peroxynitrite. At lower concentrations, NO serves regulatory roles via activation of soluble guanylate cyclase, resulting in increased cGMP levels in target cells. In vascular smooth muscle, cGMP causes relaxation by reducing [Ca2+]i and by downregulating the contractile apparatus (Fig. 2). These actions are mostly (although not exclusively; Ref. 97) mediated by type I (soluble) cGMP-dependent protein kinase (150, 398).
|
The reduction of [Ca2+]i by cGMP is accomplished in several ways. One is inhibition of calcium influx. Voltage- and receptor-operated calcium channels of the sarcolemma are directly phosphorylated and inactivated by the cGMP-dependent protein kinase (9, 28). In addition, cGMP-dependent protein kinase activates potassium channels of the sarcolemma (12, 13, 39), causing membrane hyperpolarization (13) and consequently reducing calcium influx through the voltage-operated calcium channels. In addition to the reduction of the extracellular calcium influx, cGMP also diminishes calcium release from the sarcoplasmic reticulum by blocking the inositol 1,4,5-trisphosphate-sensitive calcium release channel (186).
Enhanced calcium extrusion from the cytosol into the extracellular space also contributes to the vasorelaxant effect of cGMP. Ca2+-ATPase and the sodium/calcium exchanger of the sarcolemma are both stimulated by cGMP (108, 109). Calcium sequestration into the sarcoplasmic reticulum is also potentiated by cGMP via phospholamban-mediated activation of the Ca2+-ATPase of the sarcoplasmic reticulum (9, 374).
In vascular smooth muscle, tension depends on the phosphorylation status of the regulatory myosin light chain. Activation of the myosin light chain phosphatase is another means by which cGMP reduces vascular tone (202, 397, 398). In various tissues cGMP acts also by altering the activity of phosphodiesterases deactivating cAMP; in smooth muscle, however, this mechanism has not been documented. More details on the NO-cGMP signal transduction system can be found in extensive recent reviews (150, 246, 329).
| |
II. NITRIC OXIDE IN THE REGULATION OF THE BASAL TONE OF THE NORMAL PULMONARY VESSELS |
|---|
|
TopPreviousNextReferences
|
|---|
Because NO is a vasodilator continuously produced in many vascular beds, it has been suggested that a reduction of resting pulmonary vascular NO synthesis could be responsible for pulmonary hypertension (7, 71). Thus, to evaluate the role of NO in pulmonary hypertension, it is useful to first examine the basal NO production in the normal pulmonary circulation.
With respect to basal vascular tone, there is a qualitative contrast between the pulmonary circulation of a fetus and newborn on one side and that of an adult on the other. In the fetus, pulmonary vascular tone is similarly high as in the systemic circulation. In the neonatal period, pulmonary vascular tone decreases rapidly so that in older infants, children, and adults it is usually minimal. This review focuses primarily on the pulmonary circulation that has completed the perinatal transition from the fetal state. The role of NO in the fetal and neonatal pulmonary circulation, reviewed in detail elsewhere (2, 4, 89, 181, 307, 350), is summarized only briefly.
A. Adults
After a neonatal period, a normal, healthy pulmonary circulation is typically fully dilated. This statement is based not only on the well-known fact of a high flow and low pressure and resistance in the pulmonary circulation, but especially on a common finding that administration of vasodilators (in doses sufficient to cause profound systemic vasodilation) have very little or no effect on the pulmonary circulation of most healthy individuals (5, 69, 76, 104, 154, 317). The mechanisms responsible for this low basal tone of the pulmonary vessels are not clear. When NO was discovered as an endogenous vasodilator, an intriguing idea appeared that it could be a high continuous release of NO that keeps (or helps to keep) pulmonary vessels dilated. As discussed below, most of the data available today are not consistent with this possibility.
Approaches used to assess the role played by NO in the regulation of the normal, basal tone of the healthy pulmonary circulation include measuring pulmonary vasomotor effects of NOS inhibitors, studies of NOS mRNA and protein expression, and the use of transgenic mice.
1. Effect of NOS inhibitors
The rationale behind using NOS inhibitors is as follows. If a continuous, basal production of NO (a vasodilator) helps to keep pulmonary vascular tone and resistance low, then inhibition of this basal production should increase pulmonary vascular resistance. Analogous reasoning led to the discovery of the continuous, "tonic" release of NO in the systemic vasculature when it was noticed that administration of NOS inhibitors caused systemic vasoconstriction (114-117, 294, 377). In the pulmonary vasculature, the reported effects of NOS inhibitors are variable. It is likely that differences in species and in NOS expression in different vascular segments contribute to the discrepancies in the literature. Therefore, in an attempt to bring some order into the plethora of findings, the following discussion of the effects of NOS inhibitors on the resting pulmonary vascular tone is sorted by species and experimental preparation.
A) RAT. I) Isolated perfused lungs. The initial
attempts to elucidate the role of endothelium-derived relaxing
factor (EDRF)/NO in the pulmonary circulation were started before the
relatively selective NOS inhibitors, such as
N
-monomethyl-L-arginine
(L-NMMA) or
N-nitro-L-arginine methyl esther
(L-NAME), became available. Brashers et al.
(38) utilized the finding that EDRF activity was inhibited by the lipoxygenase antagonists eicosatetraynoic and
nordihydroguaiaretic acids and by the antioxidant hydroquinone. Using
isolated rat lungs, they found that the resting vascular tone was not
significantly altered by these substances at doses effective in
blocking the responses to endothelium-dependent vasodilators.
The first study utilizing an L-arginine-derived specific
blocker to investigate the effect of NOS inhibition on the basal pulmonary vascular tone was published by Archer et al.
(16). They found that L-NMMA (4.7 × 104 M) did not alter baseline perfusion pressure in
isolated rat lungs perfused with Krebs-albumin solution at a
constant flow rate. The same dose of L-NMMA completely
prevented the vasodilator response of preconstricted pulmonary
vasculature to bradykinin, known to be EDRF dependent (52,
107), confirming that the dose was effective in inhibiting
NOS. These data indicated that, unlike in the systemic vasculature,
there is no physiologically significant basal synthesis of NO in the
normal rat pulmonary circulation.
The finding that L-NMMA causes minimal or no
vasoconstriction is isolated rat lungs perfused with artificial
solution was subsequently independently confirmed (18,
26, 44, 74, 137)
and expanded by using other NOS inhibitors and variations of the
technique. For example, when blood was used instead of an artificial
solution as a perfusate for the isolated rat lungs, L-NMMA
again caused no physiologically significant increase in vascular
resistance (20, 23, 100,
210, 309, 362,
412). Using both salt solution- and blood-perfused rat
lungs, numerous authors found minimal or no vasoconstrictor response to
more potent NOS inhibitors, namely, L-NAME
(20, 73, 83, 134,
135, 158, 319, 359,
376, 406) and
N-nitro-L-arginine
(L-NA) (84, 134,
265, 302, 304,
318). Using a sensitive videomicroscopy system in isolated
perfused rat lungs, Suzuki, Yamaguchi, and colleagues
(359, 406) found that L-NAME
altered neither the resting pulmonary vascular resistance nor the
resting diameters of the pulmonary precapillary arterioles (20-30
µm).
A few authors found an increased vascular resistance in isolated rat
lungs after administration of L-NA (130) or
L-NAME (21, 311,
394), usually using relatively high doses (>3 × 104 M). We believe that this vasoconstriction may have
been caused predominantly by the nonspecific, NOS-unrelated effects
of higher doses (11, 40, 209,
282, 371) because lower doses, which do not
elicit pulmonary vasoconstriction, are sufficient to inhibit endothelium-dependent vasodilation (16,
74, 83, 84, 135, 158, 210, 265, 304,
318). In one study, the effects of L-NAME and
L-NA were directly compared between the lung and kidney
isolated from the same rat (134). Doses of both NOS
inhibitors, which elicited massive vasoconstriction in the kidney, had
no effect in the lung (Fig. 3). This
finding confirms the presence of a continuous NO production in the
renal circulation and its absence in the lung.
|
Dr. Taylor's group (21, 394) found a vasoconstrictor response to a relatively high dose of L-NAME in lungs perfused at constant pressure only when using higher viscosity perfusates (blood or salt solution containing >10% albumin), but not with perfusates of low viscosity. They argued that basal NO production existed in the pulmonary circulation as a result of shear stress, which was greatly reduced in lungs perfused with low viscosity solutions (because shear stress is a function of perfusate viscosity). This idea is intriguing because shear stress is a known and potent stimulus for endothelial NO production in vitro (60, 138, 167, 189, 192, 200, 236). However, Uncles et al. (376) found that even high doses of L-NAME had no effect on resting vascular tone in isolated rat lungs perfused with artificial perfusates of viscosity equal to that of the whole blood. On the other hand, in their experiments L-NAME caused pulmonary vasoconstriction when blood (even diluted, of relatively low viscosity) was used as a perfusate (376). Thus the issue of viscosity and shear stress remains controversial. In any case, these studies do not explain the findings of many authors of a minimal or no response to lower, yet effective, doses of NOS inhibitors in lungs perfused with blood (20, 23, 83, 210, 309, 319, 362, 412).
To summarize, most studies show that low doses of NOS inhibitors, effective in inhibiting endothelium-dependent vasodilation, do not cause a significant vasoconstriction in isolated perfused rat lungs.
II) Intact rats. The studies on intact rats show no significant pulmonary vasoconstrictor response to acute administration of L-NA (265) and L-NAME (98, 155) in doses (5-15 mg/kg iv) effective in increasing systemic vascular resistance. Higher doses of L-NAME (30-300 mg/kg iv) increased pulmonary arterial pressure in catheterized rats when lung flow was held constant (153). When pulmonary blood flow was not controlled, there was no significant change in pulmonary vascular resistance in response to L-NAME (153). Chronic oral treatment with L-NAME significantly increased systemic, but not pulmonary, arterial pressure in normal rats (132). L-NMMA, on the other hand, increased pulmonary vascular resistance in conscious rats when administered acutely (50 mg/kg iv) (229). The reason for this discrepancy is obscure, but it is quite likely that differences in technique do not play a role because the same laboratory using the same technique found no response to L-NAME (98) and a significant response to L-NMMA (229). One possible explanation is that L-NMMA has more nonspecific, NOS-unrelated effects than L-NA or L-NAME, and these, rather than reduction of NO synthesis, produce pulmonary vasoconstriction.
III) Isolated pulmonary arteries. Both unchanged (61, 198, 215, 265, 322, 363, 388) and increased (16, 127, 169, 322, 349, 405, 409) tension in response to NOS inhibitors have been reported in the isolated rat pulmonary arteries. Salameh et al. (322) found a constrictor response to L-NA in pulmonary arteries of one rat strain and its absence in another. Possible reasons for the discrepancies between vasoconstrictor response to NOS inhibition in many studies with isolated pulmonary arteries and its absence in most of the studies on isolated lungs or intact rats (see above) have not been directly addressed. It is likely that three factors may play a role: vessel size/type (conduit vs. resistance), resting passive tension, and precontraction by agonists.
Most of the studies in the isolated vessels utilize large, conduit arteries, which contribute relatively little to the total pulmonary vascular resistance in the whole lung. The total resistance is controlled mostly by the small, peripheral vessels (68). The large arteries express more eNOS (see sect. IIA2) and are more reactive to exogenous NO (13) than the smaller, more peripheral arteries. Several (61, 198, 215, 363), even though not all (349), studies performed on small, distal pulmonary arteries found no significant contractile response to NOS inhibitors. On the other hand, unchanged tension after administration of NOS inhibitors has also been described on several occasions in large pulmonary arteries in vitro (265, 388).
The degree of passive stretch of the vascular ring preparations is another potentially confounding factor. In most studies, the resting, passive stretch is set to a level that results in the largest constrictor response to depolarization induced by an elevation of the extracellular potassium concentration. For pulmonary arteries, the passive stretch force found in this manner is 500 mg or more, most often around 800 mg. With the use of the Laplace equation, the wall tension can be used to calculate the corresponding transmural pressure (245, 270). A stretch force of 500 mg corresponds to a transmural pressure of ~30 mmHg in the large pulmonary arteries and of ~50 mmHg in the smaller pulmonary arteries (270). In vivo, pulmonary arterial pressure above 20 mmHg is diagnosed as pulmonary hypertension (295). In other words, vasoconstrictor reactivity of the isolated pulmonary vessels is maximal at wall stretch levels corresponding to markedly elevated pulmonary arterial pressure. When this high level of wall stretch is used as a baseline, the administration of NOS inhibitors does not accurately address the problem of NO synthesis in the normal, resting pulmonary vasculature, even though vessels isolated from normal rats are used. Instead, the finding of a vasoconstrictor response to NOS inhibitors under these conditions (16, 127, 169, 349, 405, 409) indirectly supports the idea discussed below that basal NO synthesis is elevated in situations associated with increased pulmonary arterial wall tension. To yield more direct information about the role of NO in the normal, resting pulmonary vasculature, measurements would be needed of the responses to NOS inhibitors at a range of stretch values including those corresponding to the normal physiological transmural pressures. MacLean and McCulloch (215) found a negligible response of the rat pulmonary resistance arterial rings to L-NAME when transmural tension was set to 235 mg (equivalent to intravascular pressure of ~16 mmHg).
Similarly, although it is customary to use the pulmonary arterial rings precontracted with various agonists (typically, phenylephrine or norepinephrine), the nature of the interaction between the NOS inhibitors and the preexisting active tension is poorly defined. Consequently, it is not clear which degree of precontraction in vitro models the resting, usually fully dilated pulmonary circulation (5, 69, 76, 104, 154, 317) and which precontraction is more similar to a vasoconstricted state in vivo. Thus the interpretation of the results is uncertain.
B) DOG. Most of the available evidence indicates that L-NA and L-NAME do not cause pulmonary vasoconstriction in the dog. This is true in the isolated perfused left lower lobe (129), isolated whole lung (21, 64), and intact anesthetized (205) and conscious (256) dogs. On the other hand, Perrella and co-workers (278, 279) found significant pulmonary vasoconstrictor response to L-NMMA in anesthetized dogs. Thus, as in the intact rat, pulmonary vasoconstriction in dogs appears to be produced by L-NMMA, but not by L-NA or L-NAME, supporting the possibility that L-NMMA's vasoconstrictor action could be due to its more pronounced NOS-unrelated effects.
C) CAT. Originally, L-NAME (100 mg/kg iv) was shown to cause vasoconstriction in the pulmonary circulation of the cat (70, 231). The same laboratory recently published an elegant study in cats demonstrating that a novel NOS inhibitor, L-N5-(1-iminoethyl)-ornithine, increased pulmonary vascular resistance only at high doses (>10 mg/kg iv). These higher doses had no more inhibitory effect on the endothelium-dependent vasodilation to acetylcholine, bradykinin, and substance P than lower doses (1-10 mg/kg iv) that were without effect on the resting pulmonary vascular resistance (70) (Fig. 4). Thus NOS-unrelated effects of L-N5-(1-iminoethyl)-ornithine seem to be responsible for the pulmonary vasoconstriction. The authors themselves interpret their results as showing that the "basal release of NO does not play an important role in the maintenance of baseline tone in the pulmonary vascular bed of the cat" (70).
|
D) RABBIT. Data in rabbits are conflicting. On one hand, Persson and co-workers (280, 281, 392) found a significant vasoconstrictor response to L-NAME (30 mg/kg iv) in open-chest rabbits. On the other hand, other groups reported an unchanged vascular resistance in isolated rabbit lungs perfused either with a buffer solution or with blood after administration of L-NMMA (128) or L-NAME (172, 208, 400). Sprague et al. (346) suggested that erythrocytes may respond to mechanical deformation during their passage through microvessels by releasing cAMP that, in turn, evokes vascular NO synthesis. They found that rabbit and human (but not dog) erythrocytes release cAMP in response to mechanical deformation. L-NAME produced vasoconstriction in isolated rabbit lungs in the presence of human, but not dog, erythrocytes (346).
E) PIG. An increased pulmonary vascular resistance in response to L-NA and L-NAME was reported in anesthetized pigs (8, 380) and in isolated pig lungs (63, 64). However, a lack of a vasoconstrictor effect of L-NAME was also found in anesthetized pigs (77).
F) SHEEP. Today, sheep are the only species where NOS inhibitors appear to consistently cause pulmonary vasoconstriction; we are unaware of studies in which NOS inhibitors would have not increased pulmonary vascular resistance in sheep. L-NA and L-NAME (20-25 mg/kg iv) were reported to cause pulmonary vasoconstriction in an intact adult sheep (185, 211, 237) and in isolated sheep lung (64).
G) HORSE. In resting horses, L-NAME (20 mg/kg iv) caused a minimal rise in pulmonary arterial pressure (218). In this study, the pulmonary arterial pressure value before L-NAME administration is not given, but it is said to be similar to that in horses in a control study (no L-NAME given), where it was 31.3 ± 1.2 mmHg. After L-NAME administration, the pulmonary arterial pressure was 31.4 ± 1.0 mmHg. At the same time, L-NAME increased systemic blood pressure by 36 mmHg. Thus the pulmonary response to L-NAME was relatively negligible in comparison with the systemic effect. This conclusion is further reinforced by the results in exercise, showing that the pulmonary vascular pressure-flow relationship was unaffected by L-NAME (218).
H) MOUSE. In mice, acute administration of
L-NAME (100 mg/kg iv) caused systemic vasoconstriction, but
both pulmonary arterial pressure and pulmonary vascular resistance were
unchanged (354). Similarly, when L-NAME was
infused in mice by minipumps for 5 days (100 mg · kg1
· day1), systemic arterial pressure and vascular
resistance were significantly elevated, whereas pulmonary arterial
pressure and vascular resistance were not (354).
Endothelium-dependent vasodilation to acetylcholine was inhibited.
In isolated mouse lungs perfused at constant flow rate, acute
L-NA administration (104 M) did not alter
baseline perfusion pressure (80).
The mouse is a species with an advantage of a technical feasibility of
producing individuals with targeted gene disruption. Steudel et al.
(354) were the first to study the pulmonary circulation in
mice with targeted disruption of the gene encoding eNOS. As expected,
the eNOS 
/ mice had impaired endothelium-dependent vasodilator
response to acetylcholine and marked systemic hypertension. They also
had a somewhat higher mean pulmonary arterial pressure (19.0 ± 0.8 mmHg) than the wildtype mice (16.4 ± 0.6 mmHg) and significantly elevated total pulmonary resistance due to reduced cardiac output (354). Fagan and co-workers
(79, 80) confirmed that the mice with the
null mutation of the eNOS gene had increased right ventricular systolic
pressure compared with the wild-type mice. Right ventricular
systolic pressure was normal in nNOS / mice and elevated in mice
with iNOS gene disruption, although to a lesser degree than in the eNOS
/ mice (80). However, it is useful to keep in mind
that the studies by Fagan and co-workers (79,
80) were performed at an altitude of ~1,600 m. It has been shown previously that even the very mild hypoxia experienced at
that altitude is sufficient to elicit pulmonary hypertension in a
susceptible rat strain (326). It is thus possible that the elevated right ventricular systolic pressure found in eNOS / mice
in mild hypoxia (79, 80) may reflect the role
of eNOS in limiting the pulmonary hypertensive response to chronic
hypoxia (discussed in sect. IV).
It is striking in the study of Steudel et al. (354) that the transgenic eNOS-deficient mice have moderate pulmonary hypertension whereas the wild-type mice treated with NOS inhibitor have none. An explanation of this paradox can be related to the role of NO in the neonatal pulmonary circulation (see sect. IIB). Endogenous NO production is known to be essential for a successful transition of the fetal (high pressure, low flow) pulmonary circulation into the postnatal (low pressure, high flow) one (3, 59). Thus it is likely that the postnatal transition of the pulmonary circulation of the eNOS-deficient transgenic mice was impaired in a manner similar to that shown in newborn lambs treated with NOS inhibitors (3, 59). In this respect, the moderate pulmonary hypertension seen in the transgenic eNOS-deficient mice (354) appears to be a consequence of an incomplete postnatal transition of the pulmonary circulation rather than a consequence of the absent NO production at the time of measurement. In contrast, the acute and the 5-day-long treatment of the adult wild-type mice with L-NAME did not affect the neonatal development of the pulmonary circulation and only could influence the NO synthesis at around the time of measurements. Thus, with respect to studying the role of NO in the pulmonary vascular tone regulation in adults, the results with NOS inhibitors in wild-type mice could be more relevant than the results with transgenic eNOS-deficient mice, which are invaluable in confirming the importance of NO for normal development of the pulmonary circulation. This possibility is supported by the observation that the increased pulmonary vascular resistance in the transgenic eNOS-deficient mice was not reduced by exogenous NO (354).
I) HUMAN. As in other species, data on the effects of NOS inhibition on the human pulmonary circulation are somewhat conflicting.
Stamler et al. (348) reported that L-NMMA
caused pulmonary vasoconstriction in healthy human volunteers. However,
their study showed a substantially lower reactivity of the pulmonary,
compared with systemic, circulation to L-NMMA (Fig.
5). Pulmonary vascular resistance was
increased only by the highest dose used (1 mg · kg1 · min1 iv), which represented the limit tolerable by the
systemic circulation (31, 348). The pulmonary
vascular resistance increased as a result of a drop in cardiac output;
pulmonary arterial pressure was unchanged. Systemic arterial pressure
and vascular resistance were significantly increased not only by this
higher dose, but also by doses as much as 10 times lower, which had no
effect on the pulmonary vascular resistance (Fig. 5). Thus, in humans,
as in other species (see above), L-NMMA in doses sufficient
to inhibit NO production in the systemic vessels had no effect on the
pulmonary circulation. Perhaps the nonspecific, NOS-unrelated
effects of L-NMMA could be important in the pulmonary
vasoconstriction seen at high doses.
|
Using intravascular Doppler sonography, Celermajer et al. (47) observed dose-dependent decreases in segmental pulmonary blood flow in response to locally infused L-NMMA in six children with congenital heart disease and normal pulmonary vascular resistance.
Data obtained on in vitro human preparations are also inconclusive. On
one hand, a relatively high dose of L-NMMA
(104 M) did not increase tension of resting isolated
small human intrapulmonary arteries (61). On the other
hand, a vasoconstrictor response to a lower dose of L-NAME
(105 M) was found in isolated perfused human lungs
(64). Nonetheless, this response was only partially
reverted by excess L-arginine, suggesting the possibility
of participation of NOS-unrelated effects of L-NAME.
Samples of tissue obtained from human patients tend to be
inhomogeneous, possibly contributing to discrepancies among studies.
Plasma concentration of an endogenous NOS inhibitor, NG,NG-dimethylarginine, is elevated in patients with chronic renal failure to a level which inhibits NOS in vitro (378). Pulmonary hypertension does not belong among the complications of chronic renal failure (22). Although very indirect, this fact is consistent with the possibility that NO is less important in the regulation of the pulmonary than systemic vascular tone in humans.
J) INTERIM SUMMARY: EFFECTS OF NOS INHIBITORS ON BASAL PULMONARY VASCULAR TONE IN ADULTS. The studies of the effects of NOS inhibitors on the resting pulmonary vascular tone in adults of different species are summarized in Table 1. In the rat, numerous studies using the isolated buffer-perfused lungs consistently show no response to NOS inhibitors. The same finding is most often reported in blood-perfused lungs, even though a significant vasoconstriction has also been repeatedly found in this preparation. Similarly, reports of no significant response appear to prevail in the intact rat, although a vasoconstriction has also been seen. The studies on the isolated rat pulmonary arterial rings in vitro, showing both an increase and no change in tone after NOS inhibition, are difficult to evaluate conclusively because of the lack of characterization and normalization of the passive and active tension.
|
The canine pulmonary circulation is not reactive to NOS inhibitors in most studies, although again, there are exceptions. In the cat, vasoconstriction has been shown in response to L-NAME, but not to L-N5-(1-iminoethyl)-ornithine at a dose sufficient to inhibit NO-dependent vasodilation. In the rabbit, a vasoconstrictor response to NOS inhibitors has been shown in open-chest studies but not in isolated lung experiments. In pig and sheep, virtually all published studies except one (77) found a pulmonary vasoconstrictor response to NOS inhibitors. In the horse and mouse, on the other hand, there is minimal or no response to L-NAME. In humans, the limited evidence available so far appears to support the existence of a vasoconstrictor response to L-NMMA and L-NAME. However, only the highest L-NMMA dose tolerated by the systemic circulation is effective in the pulmonary circulation in conscious volunteers (348), and L-NMMA does not constrict isolated human peripheral pulmonary arterial rings in vitro (61).
Hence, in most species NOS inhibitors do not consistently cause significant pulmonary vasoconstriction in doses that minimize the risk of nonspecific effects yet are effective in NOS inhibition. However, the presence of a significant pulmonary vasoconstrictor response to NOS inhibitors has been reported more often in certain species, namely, the pig, sheep, and human. Thus the crucial question whether the response in humans is substantially similar to that in experimental animals remains without a definitive answer.
2. NOS expression
In rats, NADPH diaphorase staining (a classical method for constitutive NOS localization), immunohistochemical studies using eNOS antibodies, and in situ hybridization with eNOS mRNA probe found essentially no NOS in the endothelium of the small, peripheral pulmonary arteries (those most responsible for pulmonary vascular resistance) (173, 201, 375, 402, 403). In contrast, eNOS expression was considerable in large pulmonary vessels, while <25% of medium-sized vessels showed eNOS staining (Fig. 6). No NOS immunostaining was detected in the smooth muscle of the pulmonary vessels of all sizes (403). Inducible NOS mRNA was not detectable by reverse-transcriptase polymerase chain reaction in the pulmonary arterial wall of normal rats (44).
|
Data on NOS expression in humans are contradictory. Kobzik et al. (184) found variable NADPH diaphorase staining in the endothelium of large pulmonary arteries and no staining in the pulmonary microvasculature. That resembles the results in the rat (173, 201, 402, 403). On the other hand, Giaid and Saleh (125) reported dense eNOS immunostaining in pulmonary arteries of all sizes. Several details of their technique were challenged by Xue and Johns (401), who themselves observed only a weak eNOS immunostaining in normal human pulmonary vessels.
An interesting possible source of NO in the pulmonary circulation might be NO produced in the paranasal sinuses (213) and inhaled with each breath. When autoinhalation of nasal NO was prevented in patients recovering from open heart surgery by having them breathe through their mouth, their pulmonary vascular resistance was slightly but significantly higher than when they breathed through their nose (336). However, pulmonary vascular resistance was slightly reduced in only 4 of 12 intubated, ventilated patients (who cannot inhale NO from their nose) when the air derived from the patient's own nose was aspirated and led into the inhalation limb of the ventilator (212). Hence, this interesting idea and its relevance to the normal, healthy pulmonary circulation needs more experimental clarification.
B. Fetal and Neonatal Pulmonary Circulation
Pulmonary circulation in the fetus differs substantially from that in the adult. In the adult, where blood is oxygenated in the lung, the whole cardiac output flows through the lung at a low pressure. Vascular resistance is very low. In the fetus, the oxygenation of the blood does not take place in the lung, and the lung receives only a fraction of cardiac output at high pressure. Vascular resistance is high. In these aspects the normal fetal pulmonary circulation bears more similarities to the systemic vascular beds or to the hypertensive pulmonary circulation of the adult than to the normal adult pulmonary vascular bed. Correspondingly, the role of NO may differ between normal fetal and adult pulmonary circulation. A detailed discussion of the role of NO in the fetal and neonatal pulmonary circulation, available in relevant reviews (2, 4, 89, 181, 307, 350), is beyond the scope of this review; we briefly summarize only the aspects important for a comparison with the situation in the adult.
eNOS immunostaining is dense and eNOS mRNA level is high in the fetal pulmonary circulation; they both decrease postnatally (131, 148, 173, 258, 404). Lung eNOS mRNA levels and immunoreactivity are high in the fetal rat, highest around the first postnatal day, and minimal in adult rats (148, 173, 404) (Fig. 7). There is even evidence for iNOS expression and hemodynamically relevant activity of iNOS in the fetal pulmonary circulation (291, 404), reminiscent of the iNOS expression in pulmonary hypertension in adults (see sect. IVC). NOS inhibitors cause pulmonary vasoconstriction in fetal (3, 182, 241) and newborn (67, 88, 251, 252, 277) lambs, piglets, and guinea pigs. The magnitude of this response decreases with postnatal age (277).
|
Endogenous NO synthesis plays an important role in the transition of the pulmonary circulation from the high-resistance fetal state to the low-resistance postnatal one at birth. The postnatal decline of pulmonary vascular resistance in lambs is attenuated by acute (3, 59, 182, 241) and chronic (90) L-NA treatment. The pulmonary vasodilation at birth is caused to a great extent by the increase in lung PO2. The oxygen-induced decline in the pulmonary vascular resistance in late fetal lambs is attenuated by L-NA (49, 59, 233, 241, 364).
Thus the available evidence is consistent with the view that basal NO synthesis in the pulmonary circulation is high in the fetus, culminates at the time of birth, declines postnatally, and is relatively small during adulthood.
| |
III. ROLE OF NITRIC OXIDE IN PULMONARY VASOCONSTRICTION |
|---|
|
TopPreviousNextReferences
|
|---|
Vasoconstriction is among the factors contributing to the development of most forms of chronic pulmonary hypertension. It is therefore useful to briefly explore the NO activity during pulmonary vasoconstriction.
One of the most physiologically important pulmonary vasoconstrictor stimuli is alveolar hypoxia, and much of our knowledge of the pulmonary vasoreactivity comes from experiments studying hypoxic pulmonary vasoconstriction. Because oxygen is needed for NO synthesis, hypoxia has been hypothesized to cause pulmonary vasoconstriction by inhibiting basal NO synthesis in the pulmonary vasculature. Indeed, the apparent Michaelis constant (Km) of the eNOS for oxygen, 7.7 µM (299), predicts that NO output can be significantly reduced when PO2 drops below ~30 mmHg. However, as discussed below, there is a solid evidence available today that physiologically relevant degrees of acute hypoxia actually potentiate NO synthesis in the pulmonary circulation, as do other vasoconstrictor stimuli. This increased NO production limits the vasoconstrictor-induced increase in intravascular pressure. Apparently, the effect of the reduced substrate (O2) availability on the eNOS activity can be overridden during pulmonary vasoconstriction by other regulatory mechanisms, such as the elevated [Ca2+]i (133), at least if hypoxia is not too severe. In this context it is useful to keep in mind that in vivo, PO2 in the adult pulmonary circulation does not drop below ~30 mmHg even in hypoxia as extreme as that experienced during exercise on the summit of Mt. Everest (358).
It should also be noted that in contrast to the pulmonary vessels, the production of NO in the distal airways is reduced during ventilatory hypoxia (128). It is possible that at least a portion of this NO is produced by the neuronal isoform of NOS. Its Km for oxygen (23.2 µM) is higher than that of the endothelial isoform (299). Even less severe degrees of hypoxia therefore may suppress its activity. However, pharmacological inhibition of the airway NO production does not mimic hypoxic pulmonary vasoconstriction (128), suggesting that the hypoxic decrease in airway NO synthesis is not responsible for the increase in the pulmonary vascular tone.
The studies of the effects of NOS inhibitors on pulmonary vasoconstriction are summarized in Table 2. As already mentioned, the initial attempts to determine the role of EDRF in the pulmonary circulation started before the selective NOS inhibitors became available. It was shown that several putative blockers of the EDRF-cGMP pathway, including eicosatetraynoic and nordihydroguaiaretic acids (lipoxygenase antagonists), hydroquinone (antioxidant), and methylene blue (gyanlylate cyclase inhibitor), potentiated the hypoxic vasoconstriction in the isolated rat lungs (38, 228). The baseline tone was unaffected.
|
After the more specific, L-arginine-based NOS inibitors became available, Archer et al. (16) were the first to show that L-NMMA, while not changing the baseline vascular tone, significantly potentiates the vasoconstrictor responses of isolated rat lungs to hypoxia and angiotensin II (Fig. 8). A logical interpretation is that vasoconstriction increases the normally low NO synthesis in the pulmonary circulation. This observation was subsequently confirmed many times in isolated rat lungs using L-NMMA, L-NAME, and L-NA for NOS inhibition and hypoxia, angiotensin II, endothelin-1, dexfenfluramine, or a thromboxane analog U46619 as vasoconstrictor stimuli (18, 20, 23, 73, 83, 100, 137, 158, 210, 265, 302, 309, 359, 362, 390, 395, 406, 412). Vasoconstrictor responses to acute hypoxia and angiotensin II were also potentiated in lungs isolated from rats after treating them with L-NAME for 3 wk (132). Acute administration of L-NAME or L-NMMA potentiated hypoxic pulmonary vasoconstriction in awake (98, 229) and anesthetized (155) rats. Pulmonary vasoconstrictor response to U46619 was potentiated by L-NAME in anesthetized rats (153). NOS inhibitors added to the bath of isolated rat pulmonary arterial rings in vitro contracted by various stimuli cause further increase in tension (11, 16, 127, 169), although no change (198) or even a decrease (169, 322) in hypoxic contraction has also been observed in this preparation. Using intravital videomicroscopy, Suzuki et al. (359) observed no potentiation of the hypoxic contraction of very small pulmonary arterioles (~25 µm) by L-NAME, although the total pressor response of the whole lung was markedly increased. This suggests that NO production is stimulated only in a portion of vessels affected by vasoconstriction.
|
A potentiation of the pulmonary vasoconstrictor responses to hypoxia and U46619 by L-NA, L-NAME, or L-NMMA was observed in conscious (256) or anesthetized (41, 204, 205, 278) dogs and in isolated left lower lobe of the dog lung (129). Increased reactivity to hypoxia, U46619, or angiotensin II was also found after NOS inhibitors administration in intact (347) and open-chest rabbits (280, 281, 392) and in isolated rabbit lungs (128). Hypoxic pulmonary vasoconstriction was increased by L-NAME in intact pigs (77, 102) and by L-NMMA in isolated pig intrapulmonary arteries (263). Hypoxic pulmonary vasoconstriction potentiated by L-NMMA was also reported in human patients (31). Phenylephrine-increased tension was further elevated by L-NMMA in human small pulmonary arteries in vitro (61).
Hypoxic vasoconstriction is potentiated by L-NA in isolated
perfused mouse lungs (80). Lungs isolated from transgenic
mice with targeted disruption of the eNOS gene show hypoxic
vasoconstriction that is about twice as large as that seen in lungs of
wild-type mice, but cannot be increased further by L-NA
(80). This suggests that eNOS is the main source of NO
produced in the pulmonary circulation during acute hypoxia. Hypoxic
vasoconstriction is normal in lungs isolated from both nNOS / mice
and iNOS / mice (80).
The potentiation of pulmonary vasoconstriction by NOS inhibitors suggests that vasoconstriction increases NO synthesis in the pulmonary circulation. A more indirect proof for this conclusion was added by Cohen et al. (58). They found that hypoxic vasoconstriction was reduced in isolated rat lungs by an inhibition of cGMP phosphodiesterase, which did not change the baseline tone. Because cGMP phosphodiesterase inactivates NO's second messenger, cGMP, this finding is consistent with increased NO levels during hypoxic pulmonary vasoconstriction, although other factors than NO can elevate cGMP.
Direct measurements of NO and its oxidation products (NOx) in the lung effluent during acute hypoxia are infrequent. Grimminger et al. (128) found unchanged NOx in perfusate of isolated rabbit lungs during ventilation with a hypoxic gas, although hypoxic pulmonary vasoconstriction in that study was markedly potentiated by L-NMMA. Naoki et al. (249), on the other hand, reported a significant increase in perfusate NOx during acute hypoxia in isolated rat lung. The reason for the discrepancy is unknown, although it might be related to gradual improvements in the sensitivity of NO detection.
The mechanism whereby vasoconstriction increases NO synthesis in the pulmonary circulation has not been much studied. Wilson et al. (395) found that L-NMMA potentiated the U46619-induced vasoconstriction only in lungs perfused at constant flow, but not at constant pressure. One of the key differences between constant flow and constant pressure perfusion is that vasoconstriction increases shear stress only in the former. Therefore, these data suggest that the stimulus for increased NO synthesis during pulmonary vasoconstriction is the increase in shear stress. Shear stress is known to be a potent stimulus for endothelial NO synthesis (60, 138, 167, 189, 192, 200, 236). However, additional factors must be at play because NOS inhibitors potentiate vasoconstriction in isolated pulmonary arterial rings in vitro (11, 16, 127, 169, 265), where there are no changes in shear stress. Hypoxia itself, in the absence of changes of shear stress or vascular smooth muscle tone, increases NO synthesis in cultured pulmonary artery endothelial cells (133). Further supporting a direct, shear stress-independent influence of hypoxia on the eNOS in the pulmonary vasculature is a recent report by Le Cras et al. (200). Using rats, they found that eNOS is upregulated by chronic hypoxia equally in the normal right lung and in the left lung, in which blood flow (and therefore shear stress) had been severely reduced by creating a left pulmonary artery stenosis (see also sect. IVC).
| |
IV. NITRIC OXIDE SYNTHESIS IN CHRONIC PULMONARY HYPERTENSION |
|---|
|
TopPreviousNextReferences
|
|---|
The methods used to study the role of NO in chronic pulmonary hypertension include measurements of the effects of NOS inhibitors (or eNOS gene deficiency) on pulmonary vascular tone, measurements of NOS activity, studies of NOS expression, and evaluation of reactivity to endothelium-dependent vasodilators.
A. Effects of NOS Inhibitors
Several laboratories have shown that acute administration of L-NMMA, L-NAME, or L-NA to isolated adult rat lungs, which is usually without much effect in normal, control rats (see sect. IIA1), causes a marked vasoconstriction in lungs of rats with chronic hypoxic pulmonary hypertension (20, 158, 265, 319, 375, 376) (Fig. 9). Similar presence of a marked vasoconstrictor response to NOS inhibitors (minimal in controls) was reported in intact rats with chronic hypoxic pulmonary hypertension (155, 265) and in pulmonary arterial rings isolated from such rats (215, 265, 388). In contrast, one study found that constriction in response to L-NA was reduced by chronic hypoxia in rat conduit pulmonary artery rings in vitro (169).
|
An increase in vascular resistance in response to L-NMMA or L-NA was also found in isolated lungs of rats with pulmonary hypertension induced by an injection of an alkaloid, monocrotaline (100, 265, 375), and of a rat strain with spontaneous pulmonary hypertension (375). These findings suggest that the increased vasoconstrictor reactivity to NOS inhibitors is related to the presence of pulmonary hypertension rather than to chronic hypoxia itself. This conclusion is further supported by the observation that the hyperreactivity to NOS inhibitors persists after 2 days of recovery from chronic hypoxia (when some degree of pulmonary hypertension is still present) (265). Pulmonary resistance arterial rings isolated from chronically hypoxic rats constrict significantly in response to L-NAME only when they are passively stretched to a tension corresponding to pulmonary hypertension (215). On the other hand, vasoconstrictor response to L-NA was not found in control lungs even after increasing flow rate to such a degree that the perfusion pressure reached the level found in chronically hypoxic lungs (20, 265). That suggests that the high intravascular pressure per se is not responsible. The vasoconstrictor response to NOS blockers in isolated lungs can be prevented by endothelin receptor blockers, as has been shown in rats with pulmonary hypertension induced by chronic hypoxia (247) or monocrotaline injection (100). The authors of these studies interpreted the data as showing that endogenous NO synthesis is elevated in the hypertensive lung and opposes vasoconstriction produced by the potent endogenous pulmonary vasoconstrictor endothelin-1 (50, 199, 287), the levels of which are increased in numerous forms of pulmonary hypertension (126, 206, 352). Endothelin is a known stimulus for NO synthesis (86, 287, 410).
Aside from studies showing an increased pulmonary vasoconstrictor response to NOS inhibitors in rats with chronic hypoxic pulmonary hypertension, there are also publications reporting a lack of such a potentiation (302, 304, 318, 412). The doses of L-NMMA and L-NA in these studies were sufficient to inhibit endothelium-dependent vasodilation (304) or to potentiate reactivity to vasoconstrictor stimuli (302, 318, 412). Cremona et al. (64) found no significant difference in vasoconstrictor response to L-NAME between isolated lungs from healthy human donors and lungs of patients with pulmonary hypertension. The reason for this discrepancy from other studies is unclear. Nevertheless, it is safe to conclude that experiments studying the effects of NOS inhibitors on the resting pulmonary vascular tone in adults do not support NO deficiency in pulmonary hypertension (Table 3). In the neonates, where the role of NO in the basal pulmonary vascular tone regulation seems different than in adults (see sect. IIB), there is support both for (85) and against (29) reduced lung NO production in pulmonary hypertension.
|
Recently, mice with a targeted disruption of the eNOS gene began to be utilized to study the role of eNOS in pulmonary hypertension (79, 355). Steudel et al. (355) found that after 3-6 wk of hypoxia, several indices of pulmonary hypertension were greater in the eNOS-deficient than in the wild-type mice, including right ventricular systolic pressure, pulmonary arterial pressure, incremental total pulmonary vascular resistance, pulmonary vascular remodeling, and right ventricle free wall weight and thickness. The difference between the eNOS-deficient and wild-type mice was especially marked in the proportion of muscularized small pulmonary vessels. This proportion is often considered an essential factor determining the severity of pulmonary hypertension (297). Fagan et al. (79) reported that eNOS-deficient mice were especially sensitive to a relatively mild degree of chronic hypoxia, whereas with severe hypoxia these authors did not find right ventricular systolic pressure to be significantly different between the wild-type and genetically manipulated mice. As in the study of Steudel et al. (355), the proportion of muscularized small pulmonary vessels was increased by chronic hypoxia considerably more in the eNOS-deficient than in the wild-type mice (79).
B. Measurements of NOS Activity
Only a few studies measured NOS activity in adult pulmonary hypertension. Isaacson et al. (158) found negligible accumulation of NOx in the recirculating artificial perfusate of lungs isolated from control rats. In lungs isolated from rats with chronic hypoxic pulmonary hypertension, however, NOx accumulation in the perfusate was significantly elevated (158, 325, 375) (Fig. 10). The faster NOx accumulation in the perfusate of lungs of chronically hypoxic rats can be prevented by endothelin type B receptor antagonism (325). This suggests that endothelin-1, known to be upregulated in pulmonary hypertension (126, 206, 352), activates NOS via its action on type B receptors. Sato et al. (325) also found that perfusate NOx accumulation is not accelerated in lungs of chronically hypoxic rats if they are ventilated with anoxic gas. The relevance of this finding to less severe hypoxia, compatible with long-term survival, remains to be elucidated. Although acute hypoxia decreases otherwise elevated plasma NOx in intact rats with chronic hypoxic pulmonary hypertension (325), the contribution to this finding of NO produced in the systemic circulation is likely but unknown. The tendency for an increased release of NO into the perfusate of the isolated rat lungs did not reach significance in monocrotaline-induced pulmonary hypertension (375).
|
NOS activity in a whole lung homogenate, measured as [3H]arginine to [3H]citrulline conversion, was doubled in rats with chronic hypoxic pulmonary hypertension compared with normoxic controls in two studies (338, 403) and unchanged in the third (99). It is interesting that the increase was in the cytosolic fraction, suggesting that the isoenzyme responsible for it might have been iNOS (403). The [3H]arginine to [3H]citrulline conversion was similar in lung homogenates of normoxic and chronically hypoxic piglets (327).
Plasma concentration of the NO end-oxidation product nitrate (157) is elevated in congenital heart disease patients with high flow pulmonary hypertension (361, 383). In fact, plasma nitrate levels correlate positively with pulmonary arterial pressure (and independently also with pulmonary blood flow) in children with ventricular septal defect (361). The plasma nitrate concentration in these patients is reduced dramatically after corrective surgery (361).
NO production in the rat main pulmonary artery, measured as cGMP accumulation in the presence of inhibitors of other sources of cGMP than NO, was reduced by chronic hypoxia (339). The hemodynamic relevance of this finding, however, is probably small, as is the contribution of the main pulmonary artery to the overall resistive properties of the whole pulmonary circulation. A potentially confounding factor in this study is the extreme hyperoxia (PO2 = 680 mmHg) in which the vessels were incubated.
Although NOS activity appears elevated in most of the pulmonary vasculature in chronic pulmonary hypertension, this increase in NO production is lower than that found after activating iNOS in severe inflammation. From the published data, NO production in chronic hypoxic pulmonary hypertension can be estimated at less than ~100 nmol/h in a whole rat lung (158, 338, 375, 403) (Fig. 10). In ischemia-reperfusion injury, tissue NO concentration can reach micromolar values within hours (216).
C. NOS Expression
NADPH diaphorase staining and eNOS immunohistochemistry revealed that whereas the endothelium of the small, peripheral pulmonary arteries of normal, control rats contains little eNOS (see sect. IIA2), the same vessels are rich in eNOS in adult rats with pulmonary hypertension induced by monocrotaline injection (301, 375) or by chronic hypoxia (201, 300, 301, 375, 402, 403) (Fig. 11). The rat strain with a spontaneous form of pulmonary hypertension also shows a prominent eNOS staining in the peripheral pulmonary arteries (375). In the chronic hypoxic model, the percentage of small pulmonary vessels positive for eNOS antibody is increased, as compared with normoxic controls, as early as after 1 day of hypoxia, before any significant changes in vascular morphology can be detected (402) (Fig. 11). The percentage of eNOS-positive peripheral vessels further increases during several more days of hypoxia (402), but then it stabilizes and does not change much between 2 and 4 wk of hypoxia (403). The increase in eNOS expression in the microvasculature during pulmonary hypertension is limited to small arteries; small-venule eNOS expression does not change (300, 301). In the large pulmonary arteries, eNOS is present in both control and chronically hypoxic rats; its quantity appears higher in the latter (201, 403). It is well established that the resistive properties of the pulmonary vascular bed are mostly determined by the peripheral vessels and not much influenced by the conduit portion of the vasculature.
|
Whole lung eNOS mRNA and protein content is also increased in rats (44, 99, 201, 300, 338, 375, 402) and piglets (327) with chronic hypoxic pulmonary hypertension and in lambs with aortopulmonary shunt-induced pulmonary hypertension (29). Exposure to hypoxia as brief as 6 h is sufficient to upregulate rat lung eNOS mRNA (122). Surprisingly, only the whole lung eNOS mRNA, but not protein, is elevated in the monocrotaline model of pulmonary hypertension in rats, despite a positive eNOS immunostaining in the peripheral pulmonary arteries (375).
In addition to the increased eNOS expression in the endothelium of the peripheral pulmonary vessels, de novo iNOS mRNA and protein expression was noted in whole lung extracts and in the vascular smooth muscle of both large and small pulmonary vessels of rats (44, 155, 201, 272, 302, 402, 403) and mice (79) with chronic hypoxic pulmonary hypertension. iNOS mRNA is also increased in pulmonary endothelium of chronically hypoxic rats (272). This iNOS induction appears slower than the eNOS upregulation, because a 6-h hypoxic exposure, which increases whole lung eNOS mRNA, does not alter whole lung iNOS mRNA content (122). The functional significance of the iNOS induction in chronic hypoxic pulmonary hypertension has been questioned by recent studies showing that relatively selective inhibitors of the inducible NOS isoform, L-N6-(1-iminoethyl)lysine and aminoguanidine, had no effect on pulmonary hemodynamics of chronically hypoxic rats (302, 375).
Published data on the pulmonary vascular NOS expression in human pulmonary hypertension are rather scarce. Giaid and Saleh (125) found reduced eNOS expression in pulmonary vessels of all sizes in 46 patients with severe chronic pulmonary hypertension. Methodological factors could contribute to the discrepancy of their data with the above discussed experimental findings in rats, as suggested by Xue and Johns (401), who found increased eNOS immunostaining in two patients with pulmonary hypertension. Tuder et al. (372) studied 18 patients with various forms of pulmonary hypertension and found no decrease in eNOS immunostaining.
One factor possibly contributing to the discrepancy between the data of Giaid and Saleh (125) and animal studies is due to a focus on different stages of the progression of pulmonary hypertension. The studies using experimental animals investigate the early phases that are difficult to study in humans because pulmonary hypertension is typically diagnosed in later stages of the disease. More importantly, to study NOS expression, lung tissue must be obtained. In humans that means either using autopsy material from patients whose pulmonary hypertension had already led to death or a material from patients whose pulmonary hypertension was so severe as to require lung transplantation, or at least patients whose symptoms are serious enough to justify lung biopsy.
These three sources of human lung tissue were all used in the study of Giaid and Saleh (125), but the contribution of each source to the results was not specified. In any case, their data are from patients with very advanced or terminal stages of severe pulmonary hypertension. In such an advanced pulmonary hypertension, the pulmonary endothelium is severely damaged (386). Thus it is possible that the endothelial damage at the terminal stages of the pulmonary hypertension can reach such a level as to disable the capability of the endothelial cells to keep the NOS expression up. The elevated NOS expression of the early phases of the pulmonary hypertension (suggested by the animal experiments) may thus be overridden. This speculative interpretation is supported by the observation that the intensity of eNOS immunoreactivity correlated inversely with the severity of histological changes in the pulmonary vessels of the human patients with pulmonary hypertension (125). Recently, an increased regional heterogeneity of eNOS expression in human pulmonary hypertension has been described. Mason et al. (225) found particularly high eNOS levels in pulmonary vessels affected by plexiform lesions, whereas small arterioles free of this type of lesions had lower eNOS expression compared with healthy lungs. The studies of NOS expression in pulmonary hypertension are summarized in Table 4.
|
The cause for the increased NOS expression (where it was found) is
unclear. It could be that the decreased oxygen concentration directly
stimulates NOS gene expression in a manner similar to that shown for
several other genes, such as the genes encoding endothelin-1,
platelet-derived growth factor 
-chain, vascular endothelial
growth factor, erythropoietin, or heme oxygenase-1 (190,
323). The hypoxic induction of several of these genes is
mediated by a transcription factor known as hypoxia-inducible factor 1 (HIF-1) (96, 203, 333).
HIF-1 is a heterodimer, both subunits of which are rapidly induced by
hypoxia and quickly decay upon reoxygenation (387). The
HIF-1 binding sequence is present in the 5'-flanking region of the
murine and rat iNOS gene (235, 257,
333). Prolonged hypoxia induces HIF-1 expression in many pulmonary cell types, including endothelium and vascular smooth muscle
(272, 408). HIF-1 binding to the iNOS gene
promoter is induced in lungs of chronically hypoxic rats and in bovine
pulmonary artery endothelial cells incubated in hypoxia
(272). Hypoxia increases iNOS promoter activity in the
pulmonary artery endothelial cells, but only if the HIF-1 binding site
is intact (272). Taken together, these findings implicate
HIF-1 in the hypoxic induction of iNOS in the pulmonary circulation.
The role of HIF-1 in hypoxic regulation of expression of other NOS
isoforms has not yet been studied. The human eNOS gene promoter
contains no homology to the published binding sequence of HIF-1
(94); however, the presence of the HIF-1 binding site upstream from the published sequence cannot be excluded. The
persistence of the elevated eNOS protein and mRNA abundance in
pulmonary vessels for several days after the end of the chronic hypoxic
exposure (300) argue against a direct role of hypoxia in
eNOS upregulation. The eNOS gene promoter contains
cis-regulatory elements for activation protein 1 and nuclear
factor 
B (37, 195), transcription factors regulated (among other influences) by changes in cellular redox status,
which is proportional to oxygen availability. The nNOS gene promoter
contains the putative HIF-1 binding sites (94), but the
limited evidence available today does not support the role of nNOS in
pulmonary hypertension. The nNOS expression appears unaltered in
pulmonary vessels of patients with pulmonary hypertension (124) and in mice with chronic hypoxic pulmonary
hypertension (79).
The de novo iNOS expression in the pulmonary vascular smooth muscle could also be mediated by the activation of cytokines that are known to induce iNOS expression in vascular smooth muscle (123, 168). Both vascular wall injury and hypoxia are capable of activating various cytokines. Recent data point to the possibility that NO synthesis can be stimulated by fragments of proteins forming vascular wall matrix, the turnover of which is increased in pulmonary hypertension (see sect. VC1C). Increased intravascular pressure has been described as a stimulus for iNOS induction in systemic vessels (48); whether this mechanism plays a role in the pulmonary hypertension is unknown.
One factor to consider as possibly contributing to the eNOS upregulation is an increased shear stress of the pulmonary endothelium. In vitro, shear stress enhances both the eNOS activity (60, 138, 167, 189, 192, 200, 236) and expression (37, 94, 255, 293, 335, 367, 396, 399).
Shear stress is directly proportional to flow rate and indirectly to vessel caliber. The total blood flow through the lung usually does not change substantially in the initial phases of the pulmonary hypertension, whereas the vessel caliber decreases because of vasoconstriction and medial (and sometimes intimal) thickening. Therefore, pulmonary endothelium is probably exposed to increased shear forces during pulmonary hypertension. However, eNOS mRNA and protein expression were found identically increased in the hypoperfused left and hyperperfused right lungs of chronically hypoxic rats with surgical stenosis of the left pulmonary artery (200), implying that chronic hypoxia increases eNOS expression independently of changes in shear stress. In addition, eNOS was not found increased in normoxic rats with surgically created chronic pulmonary blood flow elevation with normal pulmonary arterial pressure (78).
D. Endothelium-Dependent Vasodilation
The role of NO in chronic pulmonary hypertension was first studied using the reactivity to endothelium-dependent vasodilators as an indicator of NO activity. However, it is important to consider that the level of a continuous, basal production of NO may be more important in terms of the mechanism of pulmonary hypertension than the response to endothelium-dependent agonists. For example, the classic endothelium-dependent vasodilator acetylcholine (106) is probably present in the pulmonary circulation in vivo only in minimal amounts because the cholinergic innervation of the resistance pulmonary vessels is scarce (305). Alterations in reactivity to a substance that the pulmonary circulation does not encounter in significant amounts in vivo may not be physiologically important. In addition, endothelium-dependent vasodilation is not always completely NO dependent; other factors, such as yet unidentified endothelium-derived hyperpolarizing factor, may participate significantly in different species and vascular beds (381), including rat lung (10). The changes in reactivity to endothelium-dependent vasodilators in chronic pulmonary hypertension may reflect altered receptor density or activity rather than or in addition to changes in NOS activity. Moreover, recent reports of increased iNOS expression in pulmonary hypertension (see sect. IVC) raise the possibility that endothelium-dependent vasodilation can be blunted by the increased iNOS activity, because it has been shown in systemic vessels (48). In fact, a paradoxical decrease in endothelium-dependent systemic vasodilation is present even in mice overexpressing the endothelial NOS isoform (264). For all these reasons, the data on endothelium-dependent vasodilation should be used for conclusions about the role of NO in pulmonary hypertension only with caution.
Many studies found a reduced reactivity to endothelium-dependent vasodilators in pulmonary hypertension. Most of these were performed using acetylcholine (or carbachol) in rings isolated from conduit pulmonary arteries of chronically hypoxic rat (45, 62, 169, 221, 223, 310). However, endothelium-independent vasodilation (to sodium nitroprusside) was also reduced in some of these studies (62, 221, 310). This argues for a reduced ability of the vascular smooth muscle to relax rather than for a decreased ability of the endothelium to produce NO in response to the agonist. The impaired reactivity to acetylcholine in pulmonary arterial rings from chronically hypoxic rats can be partially restored by cyclooxygenase inhibition (221) or by a prostaglandin H2/thromboxane A2 receptor antagonist (223), suggesting that an increased production of a vasoconstrictor prostanoid may contribute to the reduced acetylcholine reactivity. Dinh-Xuan and co-workers (71, 72) found reduced responsiveness to acetylcholine in subsegmental pulmonary arteries (1.2-3.4 mm external diameter) isolated from hypoxemic human patients with end-stage chronic obstructive lung disease. The degree of reduction correlated with the degree of vascular wall damage. Endothelium-independent vasodilator response to sodium nitroprusside was unaltered. Adnot and co-workers (7, 74) found a reduction of reactivity to acetylcholine and to a calcium ionophore A23187 (which activates eNOS in a receptor-independent manner), but not to sodium nitroprusside, in isolated perfused lungs of chronically hypoxic rats. Abolished responsiveness to acetylcholine and normal reactivity to sodium nitroprusside was reported in conduit pulmonary arteries isolated from piglets with pulmonary hypertension elicited by chronic pulmonary venous obstruction (334).
On the other hand, several studies reported unchanged pulmonary reactivity to endothelium-dependent vasodilators in pulmonary hypertension (303, 318). Still others found a significant increase (76, 99, 132, 158, 265, 268, 300, 301, 304, 384). These studies, unlike most of the studies showing inhibition of endothelium-dependent vasodilation, were done on intact pulmonary vascular bed (isolated lungs or whole animals). In fact, Orton et al. (268) demonstrated that pulmonary vasodilation in response to acetylcholine was potentiated in intact calves with chronic hypoxic pulmonary hypertension but reduced in their isolated conduit pulmonary arteries (Fig. 12). A similar finding was reported in rats by Oka et al. (265). However, MacLean and McCulloch (215) found a markedly potentiated vasodilatation in response to acetylcholine in pulmonary resistance arterial rings isolated from chronically hypoxic rats compared with normoxic controls.
|
In humans, Adnot et al. (6) found similar pulmonary vasodilator responses to acetylcholine and NO in pulmonary hypertension due to chronic obstructive lung disease, indirectly suggesting that NO-dependent vasodilation was preserved.
Taken together, it appears that in pulmonary hypertension, endothelium-dependent vasodilation is often impaired in larger pulmonary arteries, whereas in the whole adult pulmonary circulation it is, in most cases, preserved or potentiated (Table 5).
|
E. Interim Summary: Changes of NO Synthesis in Pulmonary Hypertension
The data reviewed so far indicate that pulmonary vascular NO synthesis is low when pulmonary vascular resistance is low (normal adult, see sect. IIA) and increased when pulmonary vascular resistance is increased (fetus, sect. IIB; acute pulmonary vasoconstriction, sect. III; and chronic pulmonary hypertension, sect. IV). It is likely that this elevated NO synthesis protects the thin-walled pulmonary vessels against excessive increases in intravascular pressure and a consequent danger of mechanical damage. However, it is plausible that the price for this protection is an exposure of the vascular wall to the toxic effects of the NO radical, which, when prolonged, may contribute to the vascular injury. This possibility is discussed below.
| |
V. REMODELING OF THE PULMONARY VASCULAR BED IN PULMONARY HYPERTENSION |
|---|
|
TopPreviousNextReferences
|
|---|
The mechanisms of hypertrophy and proliferation of vascular smooth muscle and deposition of matrix proteins in pulmonary hypertension have been debated for several years. The emphasis changed from the importance of physical stretch of the vascular wall and "work hypertrophy" of vascular smooth muscle due to sustained vasoconstriction to the consequences of the injury to the pulmonary vascular wall (142). In this section we discuss the experimental evidence relevant to the hypothesis that radical injury to the walls of peripheral pulmonary arteries initiates the process of vascular mesenchymal proliferation and structural remodeling. This radical injury may result from the interaction of NO and reactive oxygen species released in the injured tissue.
A. Role of Injury to the Pulmonary Vascular Wall
Injury to the alveolocapillary barrier resulting in transvascular fluid leak was described in models of pulmonary hypertension induced by hypoxia (220, 343, 351, 391), monocrotaline (152, 175, 357), increased pulmonary blood flow (289), or chronic lung embolism (366). Experimental pulmonary inflammation causes sustained pulmonary hypertension (144, 147). In patients with chronic lung diseases, pulmonary hypertension often worsens during acute respiratory attacks (87).
Lung tissue injury and inflammation are accompanied by an increased production of oxygen radical species (for review, see Refs. 179, 321). The participation of reactive radicals in the pathogenesis of chronic pulmonary hypertension ranges from an easily acceptable principle, as in the case of hyperoxia (166) and monocrotaline-induced pulmonary hypertension (174, 296), to the less intuitive possibility in the case of chronic hypoxia.
Data on oxygen radical production in acute hypoxia (minutes to hours) are contradictory; both an increase (32, 56, 91, 341, 368, 379) and a decrease were reported (14, 271). Less data are available for more chronic exposures to hypoxia (days to weeks), but they are all consistent with increased levels of oxygen radical production in the lung and their participation in the vascular remodeling of pulmonary hypertension. Nakanishi et al. (248) reported a biochemical evidence of oxidant stress in lung tissue of rats exposed to a hypoxic environment. Using a sophisticated approach of an on-line chemiluminiscence HPLC assay of phosphatidylcholine hydroperoxide, Hoshikawa et al. (151) brought a direct evidence of oxidant stress of lung tissue in chronically hypoxic rats. In addition, the authors were able to reduce hypoxic pulmonary hypertension in rats by an antioxidant N-acetyl-L-cysteine. Pulmonary artery blood pressure, right ventricle weight, and muscularization of peripheral pulmonary arteries were all lower than in untreated hypoxic rats. We have the same experience: rats given N-acetyl-L-cysteine in drinking water (20 g/100 ml) during their 2-wk exposure to hypoxia had lower pulmonary arterial blood pressure and right ventricular weight than chronically hypoxic rats not given N-acetyl-L-cysteine (140). A similar finding was reported earlier by Reid and co-workers (197). They, however, used dimethylthiourea as the antioxidant; therefore, their results have to be interpreted as evidence for participation of oxidative damage in pulmonary hypertension only with caution because of dimethylthiourea's toxicity (197). Experiments in vivo (393) and in vitro (373) showed that rat alveolar macrophages are primed to produce more reactive oxygen species after they are exposed to hypoxia for several days. Therefore, in contrast to acute hypoxia, where the reports are contradictory, it is likely that chronic hypoxia results in oxidant injury to lung vasculature.
The increased production of oxygen radicals is consistent with the vascular remodeling of pulmonary hypertension despite the experiments showing inhibition of cellular proliferation by high levels of reactive oxidant species in vitro (81). The main argument for this statement is the results of experiments with chronic hyperoxia, where the production of radical oxygen species in lung tissue is definitely increased (103, 149, 162, 342). Animals kept in hyperoxic atmosphere (>80% O2 in inspired air) develop pulmonary vascular remodeling similar to that described after exposure to hypoxic environment (166, 297).
B. Effects of NO on Radical Injury of Lung Vessels
Interactions of nitric oxide and other radicals released in tissue injury are multifaceted, and NO may oppose or enhance the oxidant tissue damage depending on relative quantities of NO and oxygen radicals produced and on the activity of antioxidant defense mechanisms. NO may reduce lung vascular damage by oxygen radicals. However, in conditions of high concentration of oxygen radical species it may act synergistically and worsen the tissue damage by products of NO and oxygen radicals interaction.
1. NO opposes oxidant lung injury
NO appears to be one of the factors that modulates the increased transvascular fluid and protein transport in lung injury. On a cellular level, the endothelial permeability was studied in vitro on a monolayer of endothelial cells. The increase in permeability was induced by H2O2. Lower amounts of NO released by 10 mM sodium nitroprusside had a protective effect. Large amounts released by a 10 times higher dose, however, worsened the endothelial barrier dysfunction (232). On a whole organ level, NO inhalation prevented oxidant injury induced by superoxide in isolated rabbit lungs; inhibition of NO production had an opposite effect (171).
An often used experimental model of lung oxidant damage in vivo is inhalation of gas mixtures containing a high concentration of oxygen. The effects of combined inhalation of NO and O2 are controversial. Some studies show that ventilation with NO and O2 reduced hyperoxic injury (230, 253); others found injury to be worsened (306). The controversy may be explained by the concentrations of NO used. In the study of Garat et al. (110), lower concentrations of NO (10 ppm) mitigated, whereas high concentrations (100 ppm) worsened hyperoxic lung injury. Combined inhalation of NO (at a very low dose of 2 ppm) and O2 was used with some benefits in patients with chronic obstructive lung disease (407). Arterial oxygenation was higher in patients treated with O2 plus NO than in patients with oxygen therapy without NO.
Studies that use NO synthesis inhibitors support the possibility of NO having a cytoprotective effect in hyperoxia. L-NAME decreased tolerance to hyperoxia in newborn (283) and adult (42) rats.
Hypoxic injury to endothelial cells induces lipid peroxidation of plasma membrane (32). NO interrupts chain reactions involved in lipid peroxidation (for review, see Ref. 313). If a local concentration of NO is higher than that of superoxide, lipid peroxidation is depressed. On the other hand, if the NO levels are exceeded by those of superoxide, NO stimulates superoxide-induced lipid peroxidation and tissue injury by converting superoxide to a highly reactive peroxynitrite (314).
NO decreases polymorphonuclear activation and adherence (238). It has been reported that NO reduces superoxide (312) and H2O2 production in activated neutrophils (93). A direct inhibition of membrane-bound NADPH-oxidase by NO (55, 93) or reduced cell viability (65) may be the explanation. The inhibitory effect depends again on the ratio of NO and oxygen radical levels. In conditions with high production of oxygen radicals, NO increases peroxynitrite formation by polymorphonuclear cells, and it enhances their ability to produce neutrophil-mediated oxidant injury (46).
2. By interacting with superoxide, NO produces more potent radicals
NO has a relatively low reactivity for a free radical species (183). Its toxicity is often a consequence of a reaction with superoxide anion to yield secondary products that are more reactive and cytotoxic.
Superoxide reacts rapidly with nitric oxide yielding peroxynitrite. The reaction is more than three times faster than dismutation by superoxide dismutase, and it is near the diffusion limit. Peroxynitrite is a short-lived substance (<1 s). Under physiological conditions it is in equilibrium with peroxynitrous acid (reviewed in Ref. 244). Peroxynitrous acid readily reacts with biological substrates similarly as hydroxyl radical.
Peroxynitrite formation from superoxide and nitric oxide occurs in vivo (24). It has been described in acute lung injury in humans (188). Production of peroxynitrite was found in several experimental diseases in animals (for review, see Ref. 360). Production of peroxynitrite was demonstrated in macrophages (159), neutrophils (43), endothelial cells (187), and vascular smooth muscle cells (35). The chemistry and biological actions of peroxynitrite have been recently reviewed (25, 313, 360).
Endothelial and vascular smooth muscle cells actively generate superoxide into the extracellular space (219, 227, 320), whereas NO freely diffuses across the cell membrane. Peroxynitrite can therefore be formed in extracellular space near the endothelial surface (24, 25). The effects of peroxynitrite may be more important on the abluminal side of the endothelium because in the vascular lumen NO is very effectively scavenged by hemoglobin.
Production of superoxide determines NO levels by controlling
peroxynitrite formation. Dismutation of superoxide increases NO
concentration in the tissue (24). Antioxidants (Cu/Zn
superoxide dismutase, ascorbate, reduced glutathione, and
-tocopherol) protect NO against superoxide anions
(207).
3. Interim conclusions: NO and lung vascular injury
The increased production of NO in pulmonary hypertension may have a protective role against radical injury to the pulmonary vascular wall. On the other hand, products of NO and oxygen radical interaction may worsen and perpetuate the vascular damage. This is especially likely to occur in the presence of an active inflammation (e.g., during acute exacerbations of chronic obstructive lung disease) in which NO production is further markedly elevated. The balance between cytotoxic and cytoprotective effects depends on relative amounts of individual radicals. The amount of radicals produced in pulmonary hypertension, however, appears lower compared with acute oxidant lung injury seen in adult respiratory distress syndrome or sepsis. In pulmonary hypertension, chronic "reparatory" mesenchymal proliferation and fibroproduction prevail.
C. Effects of NO on Remodeling of the Pulmonary Vascular Wall
1. Production of vascular matrix proteins
The fibroproduction that occurs in peripheral blood vessels during
pulmonary hypertension alters rheological properties of the pulmonary
vascular bed. In animal studies, hypoxic pulmonary hypertension was
reduced after impairment of collagen metabolism by
A) COLLAGEN SYNTHESIS. In vitro experiments on isolated
mesenchymal cells show that NO inhibits collagen formation. It has been
demonstrated in chondrocytes (260), mesangial cells
(369, 370), and pleural mesothelial cells
(269). It is questionable, however, whether the effect is
specific to collagen synthesis or whether it results from the known
nonselective inhibitory effect of high doses of NO on proteosynthesis. The suppressive effects found in vitro contrast with the results of
experiments in intact animals. Schaffer et al. (328) showed that wound fibroblasts synthesize NO. Inhibition of NOS in vivo
impaired the accumulation of collagen in the wound. It was not due to
inhibition of fibroblast proliferation. The wound NO synthesis can be
further increased by stimulation with lipopolysaccharide or
interferon- B) COLLAGEN DEGRADATION. The turnover of matrix collagen in
the walls of pulmonary arteries is increased in pulmonary hypertension (27). We have recently observed increased collagenolytic
activity in the peripheral pulmonary arteries isolated from rats with
chronic hypoxic pulmonary hypertension (259). Native
collagen molecules are degraded by matrix metalloproteinases (MMP)
(262). Our recent data indicate that a synthetic MMP
inhibitor, batimastat, reduces chronic hypoxic pulmonary hypertension
in rats (J. Herget, J. Novotná, and V. Hampl; unpublished
data). Metalloproteinases are secreted in a latent form in which a
prodomain is folded over and covers the catalytic site containing a
zinc atom. The conformation is maintained by thiol bounds between the
cysteine residues of the prodomain and zinc in the catalytic site.
Radicals including NO and peroxynitrite react with thiol groups.
Therefore, nitric oxide, oxygen radicals, and peroxynitrite may be
involved in activation of collagenolytic metalloproteinases
(292). Recent experimental evidence from in vitro experiments supports this
view. Peroxynitrite is a strong activator of human neutrophil procollagenase (MMP-8) at 1-20 × 10 Peroxynitrite at low doses also stimulated the collagenolytic activity
of MMP-2 and MMP-9 secreted by vascular smooth muscle cells
(292). Immunoblotting of activated
metalloproteinases with antinitrotyrosine antibodies showed
tyrosine nitration, which is considered a "footprint" of
peroxynitrite action (25). In the tissues, metalloproteinase activity is inhibited by specific
tissue inhibitors of metalloproteinases. Peroxynitrite fragments the
tissue inhibitor of metalloproteinase-1 (101). That may
result in an increase of collagenolytic activity. Recently Kato et al. (170) described a
peroxynitrite-promoted nitration of collagen type I in vitro. It is
not clear whether similar modification of collagen molecules appears in
vivo in vascular matrix fibers and whether it has any functional
consequences. It may be speculated that nonenzymatic modifications of
collagen molecule may decrease its resistance to proteolytic enzymes
(239). After the native collagen molecules are cleaved by specific
metalloproteinases, they can be further degraded by other nonspecific proteases (57). Collagen degradation products stimulate
lung collagen metabolism in in vitro conditions (113) and
also in intact rabbit lungs (112). Application of a
synthetic inhibitor of metalloproteinases reduced remodeling of an
injured rat carotid artery (411). Therefore, data from
various tissues suggest that increased collagen cleavage, which can be
induced by NO-derived radicals, may participate in the increased
collagen deposition in pulmonary hypertension. This possibility needs
to be verified by future experiments. C) ELASTIN. Increased lung elastolytic activity was
thoroughly studied by the group of Dr. Rabinovitch in pulmonary
hypertension induced by hypoxia (224) or monocrotaline
(365). The possible pathogenetic consequences for
development of pulmonary hypertension were reviewed recently
(290). There is little information on the effect of nitric
oxide on elastolytic activity. Kumar et al. (193) found no
effect of nitric oxide, superoxide, or H2O2 on cytokine-stimulated elastolytic activity in macrophages. Faury et
al. (82) showed that elastin degradation products elicit vasodilatation by stimulating NO production (Fig.
13). Elastin degradation products,
therefore, may participate in the increased NO release in chronic
pulmonary hypertension.
-aminopropionitrile or cis-hydroxyproline
(141, 176, 177). The amount of
collagen and elastin in the walls of blood vessels is a result of a
balance between synthesis and breakdown of these proteins. Both
processes are accelerated in pulmonary hypertension (27,
224, 234, 284).
. The stimulation of NO synthesis is followed by enhancement of collagen production (328). Similarly, there
is an increase in NO production in rat lungs with radiation-induced pneumonitis. Treatment with L-NAME decreased the
progression of radiation pneumonitis and inhibited the expression of
procollagen-1 type III mRNA in lungs (260).6 M
concentrations (266), which can exist within vascular wall in vivo (159). Exogenous NO, however, activated MMP-8
(266) and pro-MMP-1 and -9 (267) only at high
(mM) concentrations. The activation was strongly potentiated by a low
concentration of reduced glutathione (267).
View larger version (22K):
[in a new window]
Fig. 13.
Soluble fragments of elastin ( -elastin) elicit
endothelium-dependent vasodilatation in isolated aortic rings.
Endothelium-intact (top panel) and denuded (bottom
panel) aortic rings were precontracted with 106 M
norepinephrine, and 106, 104, and
103 mg/ml -elastin was added to the bath.
L-NAME (105 M) had a similar inhibitory
effect on the relaxations (not shown) as the endothelial denudation.
[Data from Faury et al. (82).]
2. Proliferation of vascular smooth muscle in peripheral pulmonary arteries
Application of authentic NO or NO donors during the development of pulmonary hypertension inhibits the proliferation of vascular smooth muscle cells in pulmonary blood vessels. Chronic hypoxic pulmonary hypertension in rats was mitigated by addition of 10 ppm NO to the hypoxic atmosphere for the whole duration of the hypoxic exposure (191). There was significantly less smooth muscle in the peripheral pulmonary arteries than in hypoxic rats not treated with NO (191). Also Roos et al. (311) reported that rats exposed to chronic hypoxia and inhalation of 20 ppm NO had a smaller remodeling of peripheral pulmonary arteries and increase in right ventricular weight than hypoxic rats not treated with NO. Unlike these morphological markers, however, the hemodynamic indices of pulmonary hypertension were unaffected by NO inhalation. As an explanation of this controversy, the authors offer an assumption that endogenous NO production is downregulated in rats who lived in an hypoxic environment enriched with NO. Because of inhibition of endogenous NO production, their vascular tone increases after the weaning from the NO-enriched environment. Attenuated proliferation of vascular smooth muscle in peripheral pulmonary arteries was shown also in neonatal rat pups exposed simultaneously to chronic hypoxia and NO (20 ppm) (308). However, Maruyama et al. (222) did not find any effect of inhalation of 10 or 40 ppm NO for more than 2 wk after the induction of pulmonary hypertension by a monocrotaline injection (222). In contrast, a continuous subcutaneous infusion of molsidomide, a NO donor drug, partially prevented the growth of pulmonary vascular smooth muscle in rats with monocrotaline-induced pulmonary hypertension (226).
There are no reports to demonstrate a prolonged therapeutic application of NO on pulmonary vascular wall structure in already developed pulmonary hypertension or during recovery of vascular changes after the relief from exposure to chronic hypoxia. Information on the effect on recovery would be of interest because hypoxia in chronic lung diseases is usually not continuous; rather, it is temporarily worsened during acute exacerbations. Mechanisms similar to those active in tissue reperfusion may play a role during the reoxygenation after exposure to hypoxia. NO can attenuate reperfusion lung injury (19, 53).
It is commonly accepted that NO inhibits proliferation of vascular smooth muscle cells in culture (118, 240, 254, 261, 337). A later work of one of these groups showed, however, that antimitotic effect of NO is restricted to cells that had been repeatedly passaged in culture (136). In a primary culture of vascular smooth muscle cells, NO stimulated mitogenesis through the amplification of fibroblast growth factor-2 production (136). Experiments in systemic vessels in vivo support the inhibitory role of NO. Increasing NO levels at the site of vascular injury by gene transfer of NOS (385) or by a local infusion of NO donor (51, 332) decreased vascular smooth muscle proliferation. Mice with targeted disruption of the eNOS gene respond to carotid artery injury with vascular smooth muscle hyperplasia, unlike the wild-type mice (316).
We reviewed above the data indicating that the lung NO production is increased in chronic hypoxic pulmonary hypertension and we argue in this section that increased NO and its interactions with other radicals may initiate the mesenchymal remodeling of the pulmonary vasculature. This is in controversy with the reports that inhalation of NO during the exposure to hypoxia attenuates vascular remodeling (191, 308, 311). We suggest two possible explanations.
First, during chronic hypoxia alone, the vascular tissue NO concentration can rise to a level which (in integration with other factors) promotes proliferation, whereas higher levels, achieved by additional exogenous NO supplementation, can be antiproliferative (perhaps due to cytotoxicity). Such a dual effect has been shown in vitro (232). The second possible explanation is related to the different factors that are at play during the early development and during the subsequent stage of a relatively stable pulmonary hypertension. During the first, progressive stage, endogenous NO can contribute to the oxidative vascular wall injury, as discussed above. Exogenous NO can be expected to aggravate this process. After approximately the first week (in the chronic hypoxic rat model), the pulmonary hypertension becomes more stable. The progressive increase in pulmonary arterial blood pressure and vascular muscularization is replaced by a near-steady state. At this point, endogenous NO may partially oppose the increased tone and, by reducing transmural tension, it can even partially reverse the previously established vascular remodeling. This effect can be potentiated by exogenous NO. This way the net effect of exogenous NO can be a reduced remodeling at the end of the exposure to chronic hypoxia despite the possibility of a potentiation of the initial insult to the vascular wall.
Apart from L-arginine being a substrate for NO synthase, it is also metabolized by arginase to urea and L-ornithine and then to polyamines (spermine, spermidine, and putrescine). These two pathways of L-arginine metabolism are linked (242). Polyamines are involved in cell growth and differentiation (for review, see Ref. 163). Although it is intriguing to speculate on possible interactions of the increased NO synthesis in pulmonary hypertension and proliferative effects of polyamines, no experimental data are available.
NO may affect vascular wall structure in other ways in addition to its influence on the radical-induced pulmonary vascular wall injury and subsequent reconstruction. It can alter or mediate the response of cultured vascular smooth muscle or endothelium to various growth factors (273, 274, 345), although a lack of such an effect has also been reported (34). There is evidence that NO stimulates the mitogen-activated protein kinase cascade (196) that is known to be involved in smooth muscle hypertrophy (reviewed in Ref. 288). The relevance of these results, obtained mostly on the systemic vessels, for pulmonary hypertension has not been systematically studied.
Prolonged exposure to elevated NO levels downregulated cGMP-dependent protein kinase (344). It has been shown that upregulation of this enzyme in vascular smooth muscle cells converts them from a dedifferentiated, "synthetic" phenotype to a more contractile-like morphology (34). It can be hypothesized that NO-induced downregulation of the cGMP-dependent protein kinase has an opposite effect on vascular smooth muscle morphology, i.e., would promote the synthetic phenotype. The vascular remodeling of pulmonary hypertension is associated with increased proportion of vascular smooth muscle cells exhibiting the synthetic phenotype (reviewed in Ref. 353). But again, the relevance of this proposed mechanism for pulmonary hypertension has not been directly addressed.
NO can cause apoptosis in vascular smooth muscle (105, 120, 161, 285, 286). Although the programmed cell death might intuitively be expected to reduce vascular wall thickness (and thus possibly act against the development of pulmonary hypertension), there is evidence of association of apoptosis with vascular wall remodeling (33, 160, 285). The cause and effect relationship is not clear at present, but one possibility could be that NO-induced apoptosis elicits reparative proliferation. Most likely, the balance between apoptosis and proliferation determines cell count in injured tissues (160). Alteration of one of these processes might be expected to result in excessive vascular wall hypertrophy. Currently, there are no studies directly linking apoptosis to the mechanism of pulmonary hypertension, but research in this direction may prove useful in near future.
3. Interim conclusions: NO and pulmonary vascular remodeling
The data concerning the involvement of NO in the vascular remodeling of pulmonary hypertension are insufficient and contradictory. Judging from experiments in various tissues, NO can have both antiproliferative and proproliferative effects. In general, experiments using repeatedly passaged cells usually show that NO inhibits growth, whereas isolated cells in primary cultures tend to proliferate in the presence of NO. Primary cultures may be closer to the in vivo situation in that the cells have not been deprived of contact with other cell types and matrix proteins for too long. The composition of matrix proteins is an important modulator of mesenchymal proliferation. An increased collagenolytic and elastolytic activity was reported in pulmonary vessels from animals with pulmonary hypertension. There are data to support the possibility that the collagenolytic and elastolytic activity can be stimulated by NO-derived radicals. Products of this activity, in turn, may potentiate NO synthesis. More experiments are needed to clarify this issue.
The finding that chronic inhalation of low concentrations of NO partly prevented experimental pulmonary hypertension suggests that the endogenous NO production, elevated in chronic hypoxic pulmonary hypertension, may have predominantly a protective effect. It is likely, however, that additional insults, such as exacerbations of hypoxia or inflammation, further increase NO production to a level at which adverse effects of NO and its related species may prevail.
| |
VI. GENERAL SUMMARY AND CONCLUSIONS |
|---|
|
TopPreviousNextReferences
|
|---|
Pulmonary hypertension is a consequence of an elevation of pulmonary vascular tone (which is normally minimal) and of thickening of the pulmonary vascular wall (which is normally thin). After a potent endogenous vasodilator, NO, was discovered, suggestions appeared that a continuous, basal production of NO keeps normal pulmonary vessels dilated. It was also speculated that reduction of this basal NO synthesis is the mechanism of pulmonary hypertension. Because chronic hypoxia occurs in many forms of pulmonary hypertension and it elicits pulmonary hypertension in experimental models, it was hypothesized that diminished availability of oxygen as a substrate for NOS reduces NO production in chronic hypoxic pulmonary hypertension.
A high basal NO production in the pulmonary vessels, however, was not confirmed by most of the subsequent experiments. A large number of studies have shown that inhibitors of NOS, which elicit a substantial vasoconstriction in the systemic vascular beds, have no significant effect in the pulmonary circulation. These findings indicate that a continuous NO release contributes to the basal tone regulation in the systemic circulation, but not in the lung vessels. This conclusion has been further strengthened by studies of NOS localization. They showed minimal NOS mRNA and protein expression in the peripheral pulmonary vessels, which are the ones mostly responsible for the overall rheological properties of the pulmonary circulation. In humans, both NOS expression in lung vessels and pulmonary vasoconstrictor reactivity to NOS inhibitors appear higher than in most experimental animals. However, humans are no exception from the observation that the role of NO in vascular tone regulation is significantly less in pulmonary than in systemic circulation.
In comparison with adults, a higher basal NO release is present in the late fetal pulmonary circulation, where pressure and resistance are high and thus resemble the situation found in adult pulmonary hypertension. NO is important in the perinatal transition of the pulmonary circulation to the low pressure state. Further studies of the mechanisms involved in this transition may help to understand the role of NO in pulmonary hypertension in adults.
Pulmonary vascular NOS expression and activity are elevated in experimental models of pulmonary hypertension in adults. In contrast, human studies with near-terminal stages of chronic pulmonary hypertension found reduced NOS expression and activity. It is likely that NO synthesis is elevated in the earlier phases of pulmonary hypertension (modeled in experimental animals) and reduced due to gross endothelial damage at advanced and terminal states (studied in humans). Unfortunately, direct measurements of NO synthesis in the pulmonary circulation are technically difficult, particularly in humans, and are done less often than needed for reliable conclusions.
All in all, the available data are consistent with the view that pulmonary vascular NO synthesis is relatively low when tone and resistance are low (in normal adults). When tone and resistance are elevated, NO synthesis in the pulmonary circulation rises. That is the case in the normal fetus and in the adult during acute vasoconstriction and (at least earlier stages of) chronic pulmonary hypertension. Traditionally, most of the research has focused on the activity of eNOS. In chronic pulmonary hypertension, vascular smooth muscle iNOS represents an additional source of NO. Because of its central location in the vascular wall, it may be more important in affecting the components of vascular media and adventitia than NO from the endothelium, which can be more easily scavenged by hemoglobin in the blood. This issue can be expected to attract more attention in future experiments.
There is evidence indicating that the primary trigger of the remodeling of peripheral lung arteries in pulmonary hypertension is an injury to the vascular wall of an oxidative nature. This injury can be worsened by NO. The combination of increased NO production with oxygen-derived radicals (also increased in pulmonary hypertension) may yield highly reactive compounds, peroxynitrite and its metabolites. Metabolism of these oxidants, once they are produced, is poorly controlled by cellular defense mechanisms. They are primarily cytotoxic and can trigger matrix protein reconstruction. However, NO can also protect against oxidant-induced injury and morphological remodeling. The ratio between local tissue levels of NO and oxygen radicals determines which effect of NO, protective or adverse, prevails. In chronic lung diseases associated with pulmonary hypertension, this balance is unstable, and cellular compensatory mechanisms may be more easily exhausted. This may be particularly true during acute attacks of respiratory infections that often interrupt the periods of tissue repair.
NO may affect the mechanism of pulmonary hypertension in more ways that just by altering the radical injury to the pulmonary vascular wall. It can influence or mediate the response of vascular smooth muscle or endothelium to various growth factors. Stimulation of the mitogen-activated protein kinase cascade by NO might also be expected to play a role. By downregulating the cGMP-dependent protein kinase, NO may contribute to the switch of the pulmonary vascular smooth muscle cells from a contractile to a synthetic phenotype, which is a known feature of vascular wall hypertrophy. The importance of NO-induced apoptosis in pulmonary hypertension is currently unknown but appears a promising direction for future research.
Selective reduction of pulmonary vascular tone by inhaled NO has been used therapeutically to overcome pulmonary hypertensive crises with remarkable success. This approach, extensively reviewed elsewhere (75, 121, 145, 180, 214), is less suitable for treatment of more chronic forms of pulmonary hypertension due to technical difficulties. In addition, given the two-faceted role of NO in the pathogenesis of pulmonary hypertension in chronic lung diseases, it may not always be beneficial. More research is needed to find out whether attempts to limit lung vascular tissue injury due to interaction of elevated endogenous NO and oxygen radicals are more appropriate in some forms of chronic pulmonary hypertension.
| |
ACKNOWLEDGMENTS |
|---|
The authors' research work was supported by the Grant Agency of the Czech Republic Grants 305/97/S070, 305/00/1432, and 306/97/0854 and Charles University Grant Agency Grant 90/1998/C/2LF.
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: J. Herget,
Dept. of Physiology, Charles University Second Medical School,
Plze
ská 130/221, 150 00 Prague 5-Motol, Czech Republic
(E-mail: jan.herget{at}lfmotol.cuni.cz).
1 Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad were jointly awarded the 1998 Nobel Prize in Physiology and Medicine for their discoveries concerning NO as a signaling molecule in the cardiovascular system.
| |
REFERENCES |
|---|
|
TopPrevious |
|---|
| 1. |
Abenhaim L,
Moride Y,
Brenot F,
Rich S,
Benichou J,
Kurz X,
Higenbottam T,
Oakley C,
Wouters E,
Aubier M,
Simonneau G, and Bégaud B.
Appetite-suppressant drugs and the risk of primary pulmonary hypertension.
N Engl J Med
335: 609-616, 1996 |
| 2. | Abman SH. Pathogenesis and treatment of neonatal and postnatal pulmonary hypertension. Curr Opin Pediatr 6: 239-247, 1994[Medline]. |
| 3. |
Abman SH,
Chatfield BA,
Hall SL, and McMurtry IF.
Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth.
Am J Physiol Heart Circ Physiol
259: H1921-H1927, 1990 |
| 4. | Abman SH, Ivy DD, Ziegler JW, and Kinsella JP. Mechanisms of abnormal vasoreactivity in persistent pulmonary hypertension of the newborn infant. J Perinatol 16 Suppl: S18-S23, 1996[Medline]. |
| 5. |
Adnot S,
Chabrier PE,
Brun-Buisson C,
Viossat I, and Braquet P.
Atrial natriuretic factor attenuates the pulmonary pressor response to hypoxia.
J Appl Physiol
65: 1975-1983, 1988 |
| 6. | Adnot S, Kouyoumdjian C, Defouilloy C, Andrivet P, Sediame S, Herigault R, and Fratacci MD. Hemodynamic and gas exchange responses to infusion of acetylcholine and inhalation of nitric oxide in patients with chronic obstructive lung disease and pulmonary hypertension. Am Rev Respir Dis 148: 310-316, 1993[Web of Science][Medline]. |
| 7. | Adnot S, Raffestin B, Eddahibi S, Braquet P, and Chabrier P-E. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest 87: 155-162, 1991. |
| 8. | Alving K, Fornhem C, and Lundberg JM. Pulmonary effects of endogenous and exogenous nitric oxide in the pig: relation to cigarette smoke inhalation. Br J Pharmacol 110: 739-746, 1993[Web of Science][Medline]. |
| 9. |
Andriantsitohaina R,
Lagaud GJ,
Andre A,
Muller B, and Stoclet JC.
Effects of cGMP on calcium handling in ATP-stimulated rat resistance arteries.
Am J Physiol Heart Circ Physiol
268: H1223-H1231, 1995 |
| 10. |
Archer SL, and Cowan NJ.
Measurement of endothelial cytosolic calcium concentration and nitric oxide production reveals discrete mechanisms of endothelium-dependent pulmonary vasodilation.
Circ Res
68: 1569-1581, 1991 |
| 11. | Archer SL, and Hampl V. NG-monomethyl-L-arginine causes nitric oxide synthesis in isolated arterial rings: trouble in paradise. Biochem Biophys Res Commun 188: 590-596, 1992[Web of Science][Medline]. |
| 12. |
Archer SL,
Huang JM-C,
Hampl V,
Nelson DP,
Shultz PJ, and Weir EK.
Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase.
Proc Natl Acad Sci USA
91: 7583-7587, 1994 |
| 13. |
Archer SL,
Huang JMC,
Reeve HL,
Hampl V,
Tolarova S,
Michelakis S, and Weir EK.
Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia.
Circ Res
78: 431-442, 1996 |
| 14. |
Archer SL,
Nelson DP, and Weir EK.
Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung.
J Appl Physiol
67: 1903-1911, 1989 |
| 15. | Archer SL, Shultz PJ, Warren JB, Hampl V, and DeMaster EG. Preparation of standards and measurement of nitric oxide, nitroxyl, and related oxidation products. Methods: A Companion to Methods Enzymol 7: 21-34, 1995. |
| 16. | Archer SL, Tolins JP, Raij L, and Weir EK. Hypoxic pulmonary vasoconstriction is enhanced by inhibition of the synthesis of an endothelium derived relaxing factor. Biochem Biophys Res Commun 164: 1198-1205, 1989[Web of Science][Medline]. |
| 17. |
Archer SL, and Weir EK.
Mechanisms in hypoxic pulmonary hypertension.
In:
Pulmonary CirculationAdvances and Controversies, edited by
Wagenvoort CA, and
Denolin H. Amsterdam: Elsevier, 1989, p. 87-113.
|
| 18. | Asano K, Yanagidaira Y, Yoshimura K, and Sakai A. The cGMP pathway is not responsible for the blunted hypoxic vasoconstriction in rat lungs after altitude exposure. Acta Physiol Scand 160: 393-400, 1997[Web of Science][Medline]. |
| 19. |
Barbotin-Larrieu F,
Mazmanian M,
Baudet B,
Detruit H,
Chapelier A,
Libert JM,
Dartevelle P, and Herve P.
Prevention of ischemia-reperfusion lung injury by inhaled nitric oxide in neonatal piglets.
J Appl Physiol
80: 782-788, 1996 |
| 20. |
Barer G,
Emery C,
Stewart A,
Bee D, and Howard P.
Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats.
J Physiol (Lond)
463: 1-16, 1993 |
| 21. |
Barnard JW,
Wilson PS,
Moore TM,
Thompson WJ, and Taylor AE.
Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs.
J Appl Physiol
74: 2940-2948, 1993 |
| 22. | Bartges JW, Willis AM, and Polzin DJ. Hypertension and renal disease. Vet Clin N Am Small Anim Pract 26: 1331-1345, 1996[Web of Science][Medline]. |
| 23. | Baudouin SV, and Evans TW. Action of carbon dioxide on hypoxic pulmonary vasoconstriction in the rat lung: evidence against specific endothelium-derived relaxing factor-mediated vasodilation. Crit Care Med 21: 740-746, 1993[Web of Science][Medline]. |
| 24. |
Beckman JS,
Beckman TW,
Chen J,
Marshall PA, and Freeman BA.
Apparent hydroxyl radical production from peroxynitrite: implications for endothelial injury by nitric oxide and superoxide.
Proc Natl Acad Sci USA
87: 1620-1624, 1990 |
| 25. |
Beckman JS, and Koppenol WH.
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.
Am J Physiol Cell Physiol
271: C1424-C1437, 1996 |
| 26. |
Bhattacharya S, and Bhattacharya J.
Segmental vascular responses to voltage-gated calcium channel potentiation in rat lung.
J Appl Physiol
73: 657-663, 1992 |
| 27. | Bishop JE, Guerreiro D, and Laurent J. Changes in the composition and metabolism of arterial collagens during the development of pulmonary hypertension in rabbits. Am Rev Respir Dis 141: 450-455, 1990[Web of Science][Medline]. |
| 28. | Bkaily G, Peyrow M, Yamamoto T, Sculptoreanu A, Jacques D, and Sperelakis N. Macroscopic Ca2+-Na+ and K+ currents in single heart and aortic cells. Mol Cell Biochem 80: 59-72, 1988[Web of Science][Medline]. |
| 29. |
Black SM,
Fineman JR,
Steinhorn RH,
Bristow J, and Soifer SJ.
Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension.
Am J Physiol Heart Circ Physiol
275: H1643-H1651, 1998 |
| 30. |
Blatter LA,
Taha Z,
Mesaros S,
Shacklock PS,
Wier WG, and Malinski T.
Simultaneous measurements of Ca2+ and nitric oxide in bradykinin-stimulated vascular endothelial cells.
Circ Res
76: 922-924, 1995 |
| 31. | Blitzer ML, Loh E, Roddy MA, Stamler JS, and Creager MA. Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol 28: 591-596, 1996[Abstract]. |
| 32. |
Block ER,
Patel JM, and Edwards D.
Mechanism of hypoxic injury to pulmonary artery endothelial cell plasma membrane.
Am J Physiol Cell Physiol
257: C223-C231, 1989 |
| 33. | Bochaton-Piallat ML, Gabbiani FRM, Desmouliere A, and Gabbiani G. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol 146: 1059-1064, 1995[Abstract]. |
| 34. | Boerth NJ, Dey NB, Cornwell TL, and Lincoln TM. Cyclic GMP-dependent protein kinase regulates vascular smooth muscle cell phenotype. J Vasc Res 34: 245-259, 1997[Web of Science][Medline]. |
| 35. |
Boota A,
Zar H,
Kim YM,
Johnson B,
Pitt B, and Davies P.
IL-1 beta stimulates superoxide and delayed peroxynitrite production by pulmonary vascular smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol
271: L932-L938, 1996 |
| 36. |
Boulanger CM,
Heymes C,
Benessiano J,
Geske RS,
Levy BI, and Vanhoutte PM.
Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: activation by angiotensin II in hypertension.
Circ Res
83: 1271-1278, 1998 |
| 37. |
Braddock M,
Schwachtgen J-L,
Houston P,
Dickson MC,
Lee MJ, and Campbell CJ.
Fluid shear stress modulation of gene expression in endothelial cells.
News Physiol Sci
13: 241-246, 1998 |
| 38. | Brashers VL, Peach MJ, and Rose CE. Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation. J Clin Invest 82: 1495-1502, 1988. |
| 39. | Brayden JE, and Nelson MT. Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 256: 534-535, 1992. |
| 40. |
Buxton ILO,
Cheek DJ,
Eckman D,
Westfall DP,
Sanders KM, and Keef KD.
NG-nitro-L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists.
Circ Res
72: 387-395, 1993 |
| 41. | Cao WB, Zeng ZP, Zhu YJ, Luo WC, and Cai BQ. Inhibition of nitric oxide synthesis increases the secretion of endothelin-1 in vivo and in cultured endothelial cells. Chin Med J 107: 822-826, 1994[Medline]. |
| 42. | Capellier G, Maupoil V, Boillot A, Kantelip JP, Rochette L, Regnard J, and Barale F. L-NAME aggravates pulmonary oxygen toxicity in rats. Eur Respir J 9: 2531-2536, 1996[Abstract]. |
| 43. | Carreras MC, Pargament GA, Catz SD, Poderoso JJ, and Boveris A. Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during respiratory burst of human neutrophils. FEBS Lett 341: 65-68, 1994[Web of Science][Medline]. |
| 44. | Carville C, Adnot S, Eddahibi S, Teiger E, Rideau D, and Raffestin B. Induction of nitric oxide synthase activity in pulmonary arteries from normoxic and chronically hypoxic rats. Eur Respir J 10: 437-445, 1997[Abstract]. |
| 45. | Carville C, Raffestin B, Eddahibi S, Blouquit Y, and Adnot S. Loss of endothelium-dependent relaxation in proximal pulmonary arteries from rats exposed to chronic hypoxia: effects of in vivo and in vitro supplementation with L-arginine. J Cardiovasc Pharmacol 22: 889-896, 1993[Web of Science][Medline]. |
| 46. | Catz SD, Carreras MC, and Poderoso JJ. Nitric oxide synthase inhibitors decrease human polymorphonuclear leukocyte luminol-dependent chemiluminiscence. Free Radical Biol 19: 741-748, 1995. |
| 47. |
Celermajer DS,
Dollery C,
Burch M, and Deanfield JE.
Role of endothelium in the maintenance of low pulmonary vascular tone in normal children.
Circulation
89: 2041-2044, 1994 |
| 48. |
Cernadas MR,
Sánchez de Miguel L,
García-Duran M,
González-Fernández F,
Millás I,
Montón M,
Rodrigo J,
Rico L,
Fernández P,
de Frutos T,
Rodríguez-Feo JA,
Guerra J,
Caramelo C,
Casado S, and López-Farré A.
Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats.
Circ Res
83: 279-286, 1998 |
| 49. |
Chang J-K,
Moore P,
Fineman JR,
Soifer SJ, and Heymann MA.
K+ channel pulmonary vasodilation in fetal lambs: role of endothelium-derived nitric oxide.
J Appl Physiol
73: 188-194, 1992 |
| 50. |
Chatfield BA,
McMurtry IF,
Hall SL, and Abman SH.
Hemodynamic effects of endothelin-1 in ovine fetal pulmonary circulation.
Am J Physiol Regulatory Integrative Comp Physiol
261: R182-R187, 1991 |
| 51. | Chen C, Hanson SR, Keefer LK, Saavedra JE, Davies KM, Hutsell TC, Hughes JD, Ku DN, and Lumsden AB. Boundary layer infusion of nitric oxide reduces early smooth muscle cell proliferation in the endarterectomized canine artery. J Surg Res 67: 26-32, 1997[Web of Science][Medline]. |
| 52. | Chen WZ, Palmer RMJ, and Moncada S. Release of nitric oxide from the rabbit aorta. J Vasc Med Biol 1: 1-6, 1989. |
| 53. | Chetham PM, Sefton WD, Bridges JP, Stevens T, and McMurtry IF. Inhaled nitric oxide pretreatment but not posttreatment attenuates ischemia-reperfusion-induced pulmonary microvascular leak. Anesthesiology 86: 895-902, 1997[Web of Science][Medline]. |
| 54. |
Chiche J-D,
Schlutsmeyer SM,
Bloch DB,
de la Monte SM,
Roberts JD,
Filippov G,
Janssens SP,
Rosenzweig A, and Bloch KD.
Adenovirus-mediated gene transfer of cGMP-dependent protein kinase increases the sensitivity of cultured vascular smooth muscle cells to the antiproliferative and pro-apoptotic effects of nitric oxide/cGMP.
J Biol Chem
273: 34263-34271, 1998 |
| 55. | Clancy RM, Leszczynaska-Piziak J, and Abramson SB. Nitric oxide, an endothelial cell relaxing factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 90: 1116-1121, 1992. |
| 56. |
Clark JM, and Lambertson CJ.
Pulmonary oxygen toxicity: a review.
Pharmacol Rev
23: 37-133, 1971 |
| 57. | Cleutjens JPM. The role of matrix metalloproteinases in heart disease. Cardiovasc Res 32: 816-821, 1996[Web of Science][Medline]. |
| 58. | Cohen AH, Hanson K, Morris K, Fouty B, McMurty IF, Clarke W, and Rodman DM. Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J Clin Invest 97: 172-179, 1996[Web of Science][Medline]. |
| 59. |
Cornfield DN,
Chatfield BA,
McQueston JA,
McMurtry IF, and Abman SH.
Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus.
Am J Physiol Heart Circ Physiol
262: H1474-H1481, 1992 |
| 60. |
Corson MA,
James NL,
Latta SE,
Nerem RM,
Berk BC, and Harrison DG.
Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress.
Circ Res
79: 984-991, 1996 |
| 61. | Crawley DE, Liu SF, Evans TW, and Barnes PJ. Inhibitory role of endothelium-derived relaxing factor in rat and human pulmonary arteries. Br J Pharmacol 101: 166-170, 1990[Web of Science][Medline]. |
| 62. |
Crawley DE,
Zhao L,
Giembycz MA,
Liu S,
Barnes PJ,
Winter RJD, and Evans TW.
Chronic hypoxia impairs soluble guanyl cyclase-mediated pulmonary arterial relaxation in the rat.
Am J Physiol Lung Cell Mol Physiol
263: L325-L332, 1992 |
| 63. |
Cremona G,
Higenbottam T,
Takao M,
Bower EA, and Hall LW.
Nature and site of action of endogenous nitric oxide in vasculature of isolated pig lungs.
J Appl Physiol
82: 23-31, 1997 |
| 64. |
Cremona G,
Wood AM,
Hall LW,
Bower EA, and Higenbottam T.
Effect of inhibitors of nitric oxide release and action on vascular tone in isolated lungs of pig, sheep, dog and man.
J Physiol (Lond)
481: 185-195, 1994 |
| 65. | Daher AH, Fortenberry JD, Owens ML, and Brown LA. Effects of exogenous nitric oxide on neutrophil oxidative function and viability. Am J Respir Cell Mol Biol 16: 407-412, 1997[Abstract]. |
| 66. | D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, and Wu M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115: 343-349, 1991. |
| 67. | Davidson D, and Eldemerdash A. Endothelium-derived relaxing factor: evidence that it regulates pulmonary vascular resistance in the isolated neonatal guinea pig lung. Pediatr Res 29: 538-542, 1991[Web of Science][Medline]. |
| 68. | Dawson CA, Linehan JH, Bronikowski TA, and Rickaby DA. Pulmonary microvascular hemodynamics: occlusion methods. In: The Pulmonary Circulation in Health and Disease, edited by Will JA, Dawson CA, Weir EK, and Buckner CK. Orlando, FL: Academic, 1987, p. 175-197. |
| 69. | de Burgh Daly I, and Hebb C. Pulmonary and Bronchial Vascular Systems: Their Reactions Under Controlled Conditions of Ventilation and Circulation. London: Edward Arnold, 1966. |
| 70. |
DeWitt BJ,
Champion HC,
Marrone JR,
McNamara DB,
Giles TD,
Greenberg SS, and Kadowitz PJ.
Differential effects of L-N5-(1-iminoethyl)-ornithine on tone and endothelium-dependent vasodilator responses.
Am J Physiol Lung Cell Mol Physiol
273: L588-L594, 1997 |
| 71. | Dinh-Xuan AT, Higenbottam TW, Clelland CA, Pepke-Zaba J, Cremona G, Butt AY, Large SR, Wells FC, and Wallwork J. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 324: 1539-1547, 1991[Abstract]. |
| 72. | Dinh-Xuan AT, Pepke-Zaba J, Butt AY, Cremona G, and Higenbottam TW. Impairment of pulmonary-artery endothelium-dependent relaxation in chronic obstructive lung disease is not due to dysfunction of endothelial cell membrane receptors nor to L-arginine deficiency. Br J Pharmacol 109: 587-591, 1993[Web of Science][Medline]. |
| 73. | Dumas JP, Dumas M, Sgro C, Advenier C, and Giudicelli JF. Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction. Eur J Pharmacol 263: 17-23, 1994[Web of Science][Medline]. |
| 74. |
Eddahibi S,
Adnot S,
Carville C,
Blouquit Y, and Raffestin B.
L-Arginine restores endothelium-dependent relaxation in pulmonary circulation of chronically hypoxic rats.
Am J Physiol Lung Cell Mol Physiol
263: L194-L200, 1992 |
| 75. | Edwards AD. The pharmacology of inhaled nitric oxide. Arch Dis Child 72: F127-F130, 1995[Web of Science]. |
| 76. | Emery CJ, Bee D, and Barer GR. Mechanical properties and reactivity of vessels in isolated perfused lungs of chronically hypoxic rats. Clin Sci 61: 569-580, 1981[Medline]. |
| 77. | Emil S, Kanno S, Berkeland J, Kosi M, and Atkinson J. Sustained pulmonary vasodilation after inhaled nitric oxide for hypoxic pulmonary hypertension in swine. J Pediatr Surg 31: 389-393, 1996[Web of Science][Medline]. |
| 78. |
Everett AD,
Le Cras TD,
Xue C, and Johns RA.
eNOS expression is not altered in pulmonary vascular remodeling due to increased pulmonary blood flow.
Am J Physiol Lung Cell Mol Physiol
274: L1058-L1065, 1998 |
| 79. | Fagan KA, Fouty BW, Tyler RC, Morris KG, Hepler LK, Sato K, LeCras TD, Abman SH, Weinberger HD, Huang PL, McMurtry IF, and Rodman DM. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 103: 291-299, 1999[Web of Science][Medline]. |
| 80. |
Fagan KA,
Tyler RC,
Sato K,
Fouty BW,
Morris KG,
Huang PL,
McMurtry IF, and Rodman DM.
Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation.
Am J Physiol Lung Cell Mol Physiol
277: L472-L478, 1999 |
| 81. | Fanburg BL, and Lee S-L. Modulation of cell proliferation by pro-oxidant stimuli. In: Nitric Oxide and Radicals in the Pulmonary Vasculature, edited by Weir EK, Archer SL, and Reeves JT. Armonk, NY: Futura, 1996, p. 233-242. |
| 82. | Faury G, Ristori MT, Verdetti J, Jacob MP, and Robert L. Effect of elastin peptides on vascular tone. J Vasc Res 32: 112-119, 1995[Web of Science][Medline]. |
| 83. |
Feng CJ,
Cheng DY,
Kaye AD,
Kadowitz PJ, and Nossaman BD.
Influence of N-nitro-L-arginine methyl ester, LY83583, glybenclamide and L158809 on pulmonary circulation.
Eur J Pharmacol
263: 133-140, 1994[Web of Science][Medline].
|
| 84. | Ferrario L, Amin HM, Sugimori K, Camporesi EM, and Hakim TS. Site of action of endogenous nitric oxide on pulmonary vasculature in rats. Pflügers Arch 432: 523-527, 1996[Web of Science][Medline]. |
| 85. |
Fike CD,
Kaplowitz MR,
Thomas CJ, and Nelin LD.
Chronic hypoxia decreases nitric oxide production and endothelial nitric oxide synthase in newborn pig lungs.
Am J Physiol Lung Cell Mol Physiol
274: L517-L526, 1998 |
| 86. | Filep JG. Endothelin peptides: biological actions and pathophysiological significance in the lung. Life Sci 52: 119-133, 1993[Web of Science][Medline]. |
| 87. | Filley GH, Bechwitt HJ, Reeves JT, and Mitchel RS. Chronic obstructive lung disease. II. Oxygen transport in two clinical types. Am J Med 44: 26-38, 1968[Web of Science][Medline]. |
| 88. |
Fineman JR,
Heymann MA, and Soifer SJ.
N-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs.
Am J Physiol Heart Circ Physiol
260: H1299-H1306, 1991 |
| 89. | Fineman JR, Soifer SJ, and Heymann MA. Nitric oxide in the developing lung. In: Nitric Oxide and the Lung, edited by Zapol WM, and Bloch KD. New York: Dekker, 1997, p. 87-95. |
| 90. | Fineman JR, Wong J, Morin FC, Wild LM, and Soifer SJ. Chronic nitric oxide inhibition in utero produces persistent pulmonary hypertension in newborn lambs. J Clin Invest 93: 2675-2683, 1994. |
| 91. | Fisher AB, Dodia C, Tan ZT, Ayene I, and Eckenhoff RG. Oxygen-dependent lipid peroxidation during lung ischemia. J Clin Invest 88: 674-679, 1991. |
| 92. | Fleming I, Bauersachs J, and Busse R. Calcium-dependent and calcium-independent activation of the endothelial NO synthase. J Vasc Res 34: 165-174, 1997[Web of Science][Medline]. |
| 93. | Forslund T, and Sundqvist T. Nitric oxide reduces hydrogen peroxide production from human polymorphonuclear neutrophils. Eur J Clin Invest 25: 9-14, 1995[Web of Science][Medline]. |
| 94. |
Förstermann U,
Boissel JP, and Kleinert H.
Expressional control of the "constitutive" isoforms of nitric oxide synthase (NOS I and NOS III).
FASEB J
12: 773-790, 1998 |
| 95. |
Förstermann U,
Closs EI,
Pollock JS,
Nakane M,
Schwarz P,
Gath I, and Kleinert H.
Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions.
Hypertension
23: 1121-1131, 1994 |
| 96. | Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, and Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604-4613, 1996[Abstract]. |
| 97. |
Fouty B,
Komalavilas P,
Muramatsu M,
Cohen A,
McMurtry IF,
Lincoln TM, and Rodman DM.
Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation.
Am J Physiol Heart Circ Physiol
274: H672-H678, 1998 |
| 98. |
Fox GA,
Paterson NAM, and McCormack DG.
Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis.
Am J Physiol Heart Circ Physiol
267: H1377-H1382, 1994 |
| 99. |
Frank DU,
Horstman DJ,
Morris GN,
Johns RA, and Rich GF.
Regulation of the endogenous NO pathway by prolonged inhaled NO in rats.
J Appl Physiol
85: 1070-1078, 1998 |
| 100. |
Frasch HF,
Marshall C, and Marshall BE.
Endothelin-1 is elevated in monocrotaline pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol
276: L304-L310, 1999 |
| 101. | Frears ER, Zhang Z, Blake DR, O'Connell JP, and Winyard PG. Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite. FEBS Lett 381: 21-24, 1996[Web of Science][Medline]. |
| 102. | Fredén F, Wei SZ, Berglund JE, Frostell C, and Hedenstierna G. Nitric oxide modulation of pulmonary blood flow distribution in lobar hypoxia. Anesthesiology 82: 1216-1225, 1995[Web of Science][Medline]. |
| 103. |
Freeman BA, and Crapo JD.
Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria.
J Biol Chem
256: 10986-10992, 1981 |
| 104. | Fritts HW, Harris P, Clauss RH, Odell JE, and Cournand A. The effect of acetylcholine on the human pulmonary circulation under normal and hypoxic conditions. J Clin Invest 37: 99-110, 1958. |
| 105. |
Fukuo K,
Hata S,
Suhara T,
Nakahashi T,
Shinto Y,
Morimoto S, and Ogihara T.
Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle.
Hypertension
27: 823-826, 1996 |
| 106. | Furchgott R, and Zawadzki J. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373-376, 1980[Medline]. |
| 107. | Furchgott RF. Role of the endothelium in the response of vascular smooth muscle to drugs. Annu Rev Pharmacol 24: 175-197, 1984[Web of Science][Medline]. |
| 108. |
Furukawa K,
Ohshima N,
Tawada-Iwata Y, and Shigekawa M.
Cyclic GMP stimulates Na+/Ca2+ exchange in vascular smooth muscle cells in primary culture.
J Biol Chem
266: 12337-12341, 1991 |
| 109. |
Furukawa K,
Tawada Y, and Shigekawa M.
Regulation of the plasma membrane Ca2+ pump by cyclic nucleotides in cultured vascular smooth muscle cells.
J Biol Chem
263: 8058-8065, 1988 |
| 110. | Garat C, Jayr C, Eddahibi S, Laffon M, Meignan M, and Adnot S. Effects of inhaled nitric oxide or inhibition of endogenous nitric oxide formation on hyperoxic lung injury. Am J Respir Crit Care Med 155: 1957-1964, 1997[Abstract]. |
| 111. |
Garcia-Cardena G,
Fan R,
Stern DF,
Liu J, and Sessa WC.
Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1.
J Biol Chem
271: 27237-27240, 1996 |
| 112. | Gardi C, Pacini A, de Santi MM, Calzoni P, Viti A, Corradeschi F, and Lungarella G. Development of interstitial lung fibrosis by long-term treatment with collagen breakdown products in rabbits. Res Commun Chem Pathol Pharmacol 68: 238-250, 1990. |
| 113. |
Gardi D,
Calzoni P,
Marcolongo P,
Cavarra E,
Vanni L, and Lungarella G.
Collagen breakdown and lung collagen metabolism: an in vitro study on fibroblast cultures.
Thorax
49: 312-318, 1994 |
| 114. |
Gardiner SM,
Compton AM,
Bennett T,
Palmer RMJ, and Moncada S.
Control of regional blood flow by endothelium-derived nitric oxide.
Hypertension
15: 486-492, 1990 |
| 115. | Gardiner SM, Compton AM, Bennett T, Palmer RMJ, and Moncada S. Persistent haemodynamic changes following prolonged infusions of NG-monomethyl-L-arginine in conscious rats. In: Nitric Oxide From L-Arginine: A Bioregulatory System, edited by Moncada S, and Higgs EA. Amsterdam: Elsevier, 1990, p. 489-491. |
| 116. | Gardiner SM, Compton AM, Bennett T, Palmer RMJ, and Moncada S. Regional haemodynamic changes during oral ingestion of NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester in conscious Brattleboro rats. Br J Pharmacol 101: 10-12, 1990[Web of Science][Medline]. |
| 117. | Gardiner SM, Kemp PA, Bennett T, Palmer RMJ, and Moncada S. Nitric oxide synthase inhibitors cause sustained, but reversible, hypertension and hindquarters vasoconstriction in Brattleboro rats. Eur J Pharmacol 213: 449-451, 1992[Web of Science][Medline]. |
| 118. | Garg UC, and Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophophate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774-1777, 1989. |
| 119. | Gaston B, Drazen JM, Loscalzo J, and Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149: 538-551, 1994[Abstract]. |
| 120. |
Geng YJ,
Wu Q,
Muszynski M,
Hansson GK, and Libby P.
Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta.
Arterioscler Thromb Vasc Biol
16: 19-27, 1996 |
| 121. | Gerlach H, and Falke KJ. Low levels of inhaled nitric oxide in acute lung injury. In: Nitric Oxide and the Lung, edited by Zapol WM, and Bloch KD. New York: Dekker, 1997, p. 271-283. |
| 122. |
Gess B,
Schricker K,
Pfeifer M, and Kurtz A.
Acute hypoxia upregulates NOS gene expression in rats.
Am J Physiol Regulatory Integrative Comp Physiol
273: R905-R910, 1997 |
| 123. | Ghezzi P, Dinarello CA, Bianchi S, Rosandich ME, Repine JE, and White CW. Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokines 3: 189-194, 1991. |
| 124. |
Giaid A.
Nitric oxide and endothelin-1 in pulmonary hypertension.
Chest
114, Suppl: 208S-212S, 1998 |
| 125. |
Giaid A, and Saleh D.
Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.
N Engl J Med
333: 214-221, 1995 |
| 126. |
Giaid A,
Yanagisawa M,
Langleben D,
Michel RP,
Levy R,
Shennib M,
Kimura S,
Masaki T,
Duguid W, and Stewart DJ.
Expression of endothelin in the lungs of patients with pulmonary hypertension.
N Engl J Med
328: 1732-1739, 1993 |
| 127. |
Greenberg B, and Kishiyama S.
Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery.
Am J Physiol Heart Circ Physiol
265: H1712-H1720, 1993 |
| 128. |
Grimminger F,
Spriestersbach R,
Weissmann N,
Walmrath D, and Seeger W.
Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs.
J Appl Physiol
78: 1509-1515, 1995 |
| 129. |
Hakim TS.
Flow-induced release of EDRF in the pulmonary vasculature: site of release and action.
Am J Physiol Heart Circ Physiol
267: H363-H369, 1994 |
| 130. |
Hakim TS,
Ferrario L,
Freedman JC,
Carlin RE, and Camporesi EM.
Segmental pulmonary vascular responses to ATP in rat lungs: role of nitric oxide.
J Appl Physiol
82: 852-858, 1997 |
| 131. |
Halbower AC,
Tuder RM,
Franklin WA,
Pollock JS,
Förstermann U, and Abman SH.
Maturation-related changes in endothelial nitric oxide synthase immunolocalization in developing ovine lung.
Am J Physiol Lung Cell Mol Physiol
267: L585-L591, 1994 |
| 132. |
Hampl V,
Archer SL,
Nelson DP, and Weir EK.
Chronic EDRF inhibition and hypoxia: effects on pulmonary circulation and systemic blood pressure.
J Appl Physiol
75: 1748-1757, 1993 |
| 133. | Hampl V, Cornfield DN, Cowan NJ, and Archer SL. Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells. Eur Respir J 8: 515-522, 1995[Abstract]. |
| 134. | Hampl V, Weir EK, and Archer SL. Endothelium-derived nitric oxide is less important for basal tone regulation in the pulmonary than the renal vessels of adult rat. J Vasc Med Biol 5: 22-30, 1994. |
| 135. | Hasséssian H, and Burnstock G. Interacting roles of nitric oxide and ATP in the pulmonary circulation of the rat. Br J Pharmacol 114: 846-850, 1995[Web of Science][Medline]. |
| 136. |
Hassid A,
Arabshahi H,
Bourcier T,
Dhaunsi GS, and Matthews C.
Nitric oxide selectively amplifies FGF-2-induced mitogenesis in primary rat aortic smooth muscle cells.
Am J Physiol Heart Circ Physiol
267: H1040-H1048, 1994 |
| 137. |
Hasunuma K,
Yamaguchi T,
Rodman DM,
O'Brien RF, and McMurtry IF.
Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs.
Am J Physiol Lung Cell Mol Physiol
260: L97-L104, 1991 |
| 138. |
Hecker M,
Mulsch A,
Bassenge E, and Busse R.
Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial autacoid release.
Am J Physiol Heart Circ Physiol
265: H828-H833, 1993 |
| 139. | Herget J. Animal models of pulmonary hypertension. Eur Respir Rev 3: 559-563, 1993. |
| 140. | Herget J, Bíbová J, and Hampl V. Antioxidant N-acetylcysteine inhibits development of hypoxic pulmonary hypertension in rats. In: INABIS '98: 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec. 7-16, 1998. Available at http://www. mcmaster.ca/inabis98/oxidative/herget0589/index. |
| 141. |
Herget J, and Hampl V.
Pulmonary circulation.
In:
Biomechanics of the Cardiovascular System, edited by
 rámek BB,
Valenta J, and
Klime F. Prague: Czech Technical Univ. Press, 1995, p. 327-336.
|
| 142. |
Herget J, and Je ek V.
Pulmonary hypertension in lung disease.
In:
Pulmonary CirculationAdvances and Controversies, edited by
Wagenvoort CA, and
Denolin H. Amsterdam: Elsevier, 1989, p. 149-189.
|
| 143. | Herget J, and Palecek F. Experimental chronic pulmonary hypertension. Int Rev Exp Pathol 18: 347-406, 1978[Medline]. |
| 144. |
Herget J,
Pale ek F,
Preclík P,
 ermáková M,
Vízek M, and Petrovická M.
Pulmonary hypertension induced by repeated pulmonary inflammation in the rat.
J Appl Physiol
51: 755-761, 1981 |
| 145. |
Higenbottam T.
Inhaled nitric oxidea magic bullet.
Q J Med
86: 555-558, 1993 |
| 146. | Higenbottam T, and Cremona G. Acute and chronic hypoxic pulmonary hypertension. Eur Respir J 6: 1207-1212, 1993. |
| 147. |
Hill NS,
O'Brien R, and Rounds S.
Repeated lung injury due to -naphtylthiourea causes right ventricular hypertrophy in rats.
J Appl Physiol
56: 388-396, 1984 |
| 148. | Hislop AA, Springall DR, Buttery LD, Pollock JS, and Haworth SG. Abundance of endothelial nitric oxide synthase in newborn intrapulmonary arteries. Arch Dis Child 73: F17-F21, 1995[Web of Science]. |
| 149. |
Ho YS,
Dey MS, and Crapo JD.
Antioxidant enzyme expression in rat lungs during hyperoxia.
Am J Physiol Lung Cell Mol Physiol
270: L810-L818, 1996 |
| 150. | Hobbs AJ, and Ignarro LJ. The nitric oxide-cyclic GMP signal transduction system. In: Nitric Oxide and the Lung, edited by Zapol WM, and Bloch KD. New York: Dekker, 1997, p. 1-57. |
| 151. | Hoshikawa Y, Ono S, Tanita S, Sakuma T, Noda M, Tabata T, Ueda S, Ashino Y, and Fujimura S. Contribution of oxidative stress to pulmonary hypertension induced by chronic hypoxia. Nippon Kyobu Shikkan Gakkai Zasshi 33: 1169-1173, 1995. |
| 152. | Hurley JV, and Jago MV. Pulmonary oedema in rats given dehydromonocrotaline: a topographic electron microscope study. J Pathol 117: 23-82, 1975[Web of Science][Medline]. |
| 153. |
Hyman AL,
Hao QZ,
Tower A,
Kadowitz PJ,
Champion HC,
Gumusel B, and Lippton H.
Novel catheterization technique for the in vivo measurement of pulmonary vascular responses in rats.
Am J Physiol Heart Circ Physiol
274: H1218-H1229, 1998 |
| 154. |
Hyman AL, and Kadowitz PJ.
Tone-dependent responses to acetylcholine in the feline pulmonary vascular bed.
J Appl Physiol
64: 2002-2009, 1988 |
| 155. | Igari H, Tatsumi K, Sugito K, Kasahara Y, Saito M, Tani T, Kimura H, and Kuriyama T. Role of EDRF in pulmonary circulation during sustained hypoxia. J Cardiovasc Pharmacol 31: 299-305, 1998[Web of Science][Medline]. |
| 156. | Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30: 535-560, 1990[Web of Science][Medline]. |
| 157. |
Ignarro LJ,
Fukuto JM,
Griscavage JM,
Rogers NE, and Byrns RE.
Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine.
Proc Natl Acad Sci USA
90: 8103-8107, 1993 |
| 158. |
Isaacson TC,
Hampl V,
Weir EK,
Nelson DP, and Archer SL.
Increased endothelium-derived nitric oxide in hypertensive pulmonary circulation of chronically hypoxic rats.
J Appl Physiol
76: 933-940, 1994 |
| 159. | Ischiropoulos H, Zhu L, and Beckman JS. Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys 298: 446, 1992[Web of Science][Medline]. |
| 160. |
Isner JM,
Kearney M,
Bortman S, and Passeri J.
Apoptosis in human atherosclerosis and restenosis.
Circulation
91: 2703-2711, 1995 |
| 161. |
Iwashina M,
Shichiri M,
Marumo F, and Hirata Y.
Transfection of inducible nitric oxide synthase gene causes apoptosis in vascular smooth muscle cells.
Circulation
98: 1212-1218, 1998 |
| 162. | Jamieson DD. Lipid peroxidation in brain and lungs from mice exposed to hypoxia. Biochem Pharmacol 41: 749-756, 1991[Web of Science][Medline]. |
| 163. | Janne J, Alhonen L, and Leinonen P. Polyamines: from molecular biology to clinical applications. Ann Med 23: 241-259, 1991[Web of Science][Medline]. |
| 164. | Janssens SP, Bloch KD, Nong ZX, Gerard RD, Zoldhelyi P, and Collen D. Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. J Clin Invest 98: 317-324, 1996[Web of Science][Medline]. |
| 165. |
Jensen KS,
Micco AJ,
Czartolomna J,
Latham L, and Voelkel NF.
Rapid onset of hypoxic vasoconstriction in isolated lungs.
J Appl Physiol
72: 2018-2023, 1992 |
| 166. | Jones R, Zapol WM, and Reid L. Pulmonary artery remodeling and pulmonary hypertension after exposure to hyperoxia for 7 days. A morphometric and hemodynamic study. Am J Pathol 117: 273-285, 1984[Abstract]. |
| 167. |
Kanai AJ,
Strauss HC,
Truskey GA,
Crews AL,
Grunfeld S, and Malinski T.
Shear stress induces ATP-independent transient nitric oxide release from vascular endothelial cells, measured directly with a porphyrinic microsensor.
Circ Res
77: 284-293, 1995 |
| 168. | Karakurum M, Shreeniwas R, Chen J, Pinsky D, Yan SD, Anderson M, Sunouchi K, Major J, Hamilton T, and Kuwabara K. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest 93: 1564-1570, 1994. |
| 169. | Karamsetty VSNMR, MacLean MR, McCulloch KM, Kane KA, and Wadsworth RM. Hypoxic constrictor response in the isolated pulmonary artery from chronically hypoxic rats. Respir Physiol 105: 85-93, 1996[Web of Science][Medline]. |
| 170. | Kato Y, Ogino Y, Aoki T, Uchida K, Kawakishi S, and Osawa T. Phenolic antioxidants prevent peroxynitrite-derived collagen modification in vitro. J Agric Food Chem 45: 3004-3009, 1997[Web of Science]. |
| 171. |
Kavanagh BP,
Mouchawar A,
Goldsmith J, and Pearl RG.
Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury.
J Appl Physiol
76: 1324-1329, 1994 |
| 172. | Kavanagh BP, Thompson JS, and Pearl RG. Inhibition of endogenous nitric oxide synthase potentiates nitrovasodilators in experimental pulmonary hypertension. Anesthesiology 85: 860-866, 1996[Web of Science][Medline]. |
| 173. |
Kawai N,
Bloch DB,
Filippov G,
Rabkina D,
Suen H-C,
Losty PD,
Janssens SP,
Zapol WM,
De la Monte S, and Bloch KD.
Constitutive endothelial nitric oxide synthase gene expression is regulated during lung development.
Am J Physiol Lung Cell Mol Physiol
268: L589-L595, 1995 |
| 174. | Kay JM. Dietary pulmonay hypertension. Thorax 49, Suppl: S33-S38, 1994. |
| 175. |
Kay JM,
Harris P, and Heath D.
Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds.
Thorax
22: 176-179, 1967 |
| 176. |
Kerr JS,
Riley DJ,
Frank MM,
Trelstad RL, and Frankel HM.
Reduction of chronic hypoxic pulmonary hypertension in the rat by beta-aminopropionitrile.
J Appl Physiol
57: 1760-1766, 1984 |
| 177. | Kerr JS, Ruppert CL, Tozzi CA, Neubauer JA, Frankel HM, Yu SY, and Riley DJ. Reduction of chronic hypoxic pulmonary hypertension in the rat by an inhibitor of collagen production. Am Rev Respir Dis 135: 300-306, 1987[Web of Science][Medline]. |
| 178. | Kiechle FL, and Malinski T. Nitric oxide: biochemistry, pathophysiology, and detection. Am J Clin Pathol 100: 567-575, 1993[Web of Science][Medline]. |
| 179. | Kinnula VL, Crapo JD, and Raivo KO. Generation and disposal of reactive oxygen metabolites in the lung. Lab Invest 73: 3-19, 1995[Web of Science][Medline]. |
| 180. | Kinsella JP, and Abman SH. Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 126: 853-864, 1995[Web of Science][Medline]. |
| 181. | Kinsella JP, and Abman SH. Physiological and therapeutic roles of nitric oxide in the transitional pulmonary circulation. In: Nitric Oxide and Radicals in the Pulmonary Vasculature, edited by Weir EK, Archer SL, and Reeves JT. Armonk, NY: Futura, 1996, p. 447-462. |
| 182. |
Kinsella JP,
Ivy DD, and Abman SH.
Ontogeny of NO activity and response to inhaled NO in the developing ovine pulmonary circulation.
Am J Physiol Heart Circ Physiol
267: H1955-H1961, 1994 |
| 183. | Knowles RG, and Moncada S. Nitric oxide as a signal in blood vessels. Trends Biochem 17: 399-402, 1992[Web of Science][Medline]. |
| 184. | Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, and Stamler JS. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol 9: 371-377, 1993. |
| 185. | Koizumi T, Gupta R, Banerjee M, and Newman JH. Changes in pulmonary vascular tone during exercise: effects of nitric oxide (NO) synthase inhibition, L-arginine infusion, and NO inhalation. J Clin Invest 94: 2275-2282, 1994. |
| 186. |
Komalavilas P, and Lincoln TM.
Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase.
J Biol Chem
269: 8701-8707, 1994 |
| 187. | Kooy NW, and Royall JA. Agonist-induced peroxynitrite production from endothelial cells. Arch Biochem Biophys 310: 352-359, 1994[Web of Science][Medline]. |
| 188. | Kooy NW, Royall JA, Ye YZ, Kelly DR, and Beckman JS. Evidence for in vivo peroxynitrite production in human acute lung injury. Am J Respir Crit Care Med 151: 1250-1254, 1995[Abstract]. |
| 189. | Korenaga R, Ando J, Tsuboi H, Yang W, Sakuma I, Toyo-oka T, and Kamiya A. Laminar flow stimulates ATP- and shear stress-dependent nitric oxide production in cultured bovine endothelial cells. Biochem Biophys Res Commun 198: 213-219, 1994[Web of Science][Medline]. |
| 190. | Kourembanas S, Morita T, Liu YX, and Christou H. Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. Kidney Int 51: 438-443, 1997[Web of Science][Medline]. |
| 191. | Kouyoumdjian C, Adnot S, Levame M, Eddahibi S, Bousbaa H, and Raffestin B. Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats. J Clin Invest 94: 578-584, 1994. |
| 192. |
Kuchan MJ,
Jo H, and Frangos JA.
Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells.
Am J Physiol Cell Physiol
267: C753-C758, 1994 |
| 193. | Kumar R, Dong Z, and Fidler IJ. Differential regulation of metalloelastase activity in murine peritoneal macrophages by granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor. J Immunol 157: 5104-5111, 1996[Abstract]. |
| 194. | Laitinen M, Zachary I, Breier G, Pakkanen T, Hakkinen T, Luoma J, Abedi H, Risau W, Soma M, Laakso M, Martin JF, and Ylaherttuala S. VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries. Hum Gene Ther 8: 1737-1744, 1997[Web of Science][Medline]. |
| 195. | Lamas S, Navarro-Antolín J, Hernández-Perera O, López-Ongil S, Rodríguez-Puyol M, and Rodríguez-Puyol D. Cyclosporine A and tacrolimus upregulate eNOS expression: role of reactive oxygen species and AP-1 (Abstract). Physiologist 41: 270, 1998. |
| 196. |
Lander HM,
Jacovina AT,
Davis RJ, and Tauras JM.
Differential activation of mitogen-activated protein kinases by nitric oxide-related species.
J Biol Chem
271: 19705-19709, 1996 |
| 197. | Langleben D, Fox RB, Jones RC, and Reid LM. Effects of dimethylthiourea on chronic hypoxia-induced pulmonary arterial remodelling and ventricular hypertrophy in rats. Clin Invest Med 12: 235-240, 1989[Medline]. |
| 198. |
Leach RM,
Robertson TP,
Twort CHC, and Ward JPT.
Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries.
Am J Physiol Lung Cell Mol Physiol
266: L223-L231, 1994 |
| 199. | Leach RM, Twort CH, Cameron IR, and Ward JPT. The mechanism of action of endothelin-1 on small pulmonary arterial vessels. Pulmon Pharmacol 3: 103-109, 1990[Medline]. |
| 200. | Le Cras TD, Tyler RC, Horan MP, Morris KG, Tuder RM, McMurtry IF, Johns RA, and Abman SH. Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase expression in the adult rat lung. J Clin Invest 101: 795-801, 1998[Web of Science][Medline]. |
| 201. |
Le Cras TD,
Xue C,
Rengasamy A, and Johns RA.
Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung.
Am J Physiol Lung Cell Mol Physiol
270: L164-L170, 1996 |
| 202. |
Lee MR,
Li L, and Kitazawa T.
Cyclic GMP causes Ca2+ desensitization in vascular smooth muscle by activating the myosin light chain phosphatase.
J Biol Chem
272: 5063-5068, 1997 |
| 203. |
Lee PJ,
Jiang BH,
Chin BY,
Iyer NV,
Alam J,
Semenza GL, and Choi AM.
Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.
J Biol Chem
272: 5375-5381, 1997 |
| 204. |
Leeman M,
de Beyl VZ,
Biarent D,
Maggiorini M,
Mélot C, and Naeije R.
Inhibition of cyclooxygenase and nitric oxide synthase in hypoxic vasoconstriction and oleic acid-induced lung injury.
Am J Respir Crit Care Med
159: 1383-1390, 1999 |
| 205. |
Leeman M,
De Beyl VZ,
Delcroix M, and Naeije R.
Effects of endogenous nitric oxide on pulmonary vascular tone in intact dogs.
Am J Physiol Heart Circ Physiol
266: H2343-H2347, 1994 |
| 206. |
Li H,
Chen S-J,
Chen Y-F,
Meng QC,
Durand J,
Oparil S, and Elton TS.
Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia.
J Appl Physiol
77: 1451-1459, 1994 |
| 207. | Lilley E, and Gibson A. Antioxidant protection of NO-induced relaxations of the mouse anococcygeus against inhibition by superoxide anions, hydroquinone and carboxy-PTIO. Br J Pharmacol 119: 432-438, 1996[Web of Science][Medline]. |
| 208. |
Lindeborg DM,
Kavanagh BP,
Van Meurs K, and Pearl RG.
Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance.
J Appl Physiol
78: 341-348, 1995 |
| 209. |
Lippton HL,
Hao Q, and Hyman A.
L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation.
J Appl Physiol
73: 2432-2439, 1992 |
| 210. | Liu SF, Crawley DE, Barnes PJ, and Evans TW. Endothelium-derived relaxing factor inhibits hypoxic pulmonary vasoconstriction in rats. Am Rev Respir Dis 143: 32-37, 1991[Web of Science][Medline]. |
| 211. | Lorente JA, Landin L, Renes E, De Pablo R, Jorge P, Rodena E, and Liste D. Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med 21: 759-767, 1993[Web of Science][Medline]. |
| 212. | Lundberg JO, Settergren G, Gelinder S, Lundberg JM, Alving K, and Weitzberg E. Inhalation of nasally derived nitric oxide modulates pulmonary function in humans. Acta Physiol Scand 158: 343-347, 1996[Web of Science][Medline]. |
| 213. | Lundberg JON, Farkas-Szallasi T, Weitzberg E, Rinder J, Lindholm J, Änggard A, Hökfelt T, Lundberg JM, and Alving K. High nitric oxide production in human paranasal sinuses. Nature Med 1: 370-373, 1995[Web of Science][Medline]. |
| 214. | Lunn RJ. Inhaled nitric oxide therapy. Mayo Clin Proc 70: 247-255, 1995[Web of Science][Medline]. |
| 215. | MacLean MR, and McCulloch KM. Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia. Br J Pharmacol 123: 991-999, 1998[Web of Science][Medline]. |
| 216. | Malinski T, Bailey F, Zhang ZG, and Chopp M. Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13: 355-358, 1993[Web of Science][Medline]. |
| 217. | Malinski T, and Taha Z. Nitric oxide release from a single cell measured in situ by a porphrinic-based microsensor. Nature 358: 676-678, 1992[Medline]. |
| 218. |
Manohar M, and Goetz TE.
L-NAME does not affect exercise-induced pulmonary hypertension in thoroughbred horses.
J Appl Physiol
84: 1902-1908, 1998 |
| 219. | Marshall C, Mamary AJ, Verhoeven AJ, and Marshall BE. Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction. Am J Respir Cell Mol Biol 15: 633-644, 1996[Abstract]. |
| 220. | Martin DJ, Baconnier L, Benchetrit G, Royer F, and Grimbert FA. Effect of acute hypoxia on lung fluid balance in the prerecruited dog lung. Bull Physiopathol Respir 22: 335-340, 1986. |
| 221. |
Maruyama J, and Maruyama K.
Impaired nitric oxide-dependent responses and their recovery in hypertensive pulmonary arteries of rats.
Am J Physiol Heart Circ Physiol
266: H2476-H2488, 1994 |
| 222. |
Maruyama J,
Maruyama K,
Mitani Y,
Kitabatake M,
Yamauchi T, and Miyasaka K.
Continuous low-dose NO inhalation does not prevent monocrotaline-induced pulmonary hypertension in rats.
Am J Physiol Heart Circ Physiol
272: H517-H524, 1997 |
| 223. |
Maruyama J,
Yokochi A,
Maruyama K, and Nosaka S.
Acetylcholine-induced endothelium-derived contracting factor in hypoxic pulmonary hypertensive rats.
J Appl Physiol
86: 1687-1695, 1999 |
| 224. |
Maruyama K,
Ye C,
Woo M,
Venkatacharya H,
Lines LD,
Silver MH, and Rabinovitch M.
Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity.
Am J Physiol Heart Circ Physiol
261: H1716-H1726, 1991 |
| 225. | Mason NA, Springall DR, Burke M, Pollock J, Mikhail G, Yacoub MH, and Polak JM. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 185: 313-318, 1998[Web of Science][Medline]. |
| 226. | Mathew R, and Altura BM. Physiology and pathophysiology of pulmonary circulation. Microcirc Endoth Lymph 6: 211-251, 1990. |
| 227. | Matsubara T, and Ziff M. Superoxide anion release by human endothelial cells: synergism betwen phorbol ester and calcium ionophore. J Cell Physiol 127: 207-210, 1986[Web of Science][Medline]. |
| 228. |
Mazmanian GM,
Audet B,
Brink C,
Cerrina J,
Kirkiacharian S, and Weiss M.
Methylene blue potentiates vascular reactivity in isolated rat lungs.
J Appl Physiol
66: 1040-1045, 1989 |
| 229. |
McCormack DG, and Paterson NAM.
Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide.
Am J Physiol Heart Circ Physiol
265: H1523-H1528, 1993 |
| 230. |
McElroy MC,
Wiener-Kronish JP,
Miyazaki H,
Sawa T,
Modelska K,
Dobbs LG, and Pittet JF.
Nitric oxide attenuates lung endothelial injury caused by sublethal hyperoxia in rats.
Am J Physiol Lung Cell Mol Physiol
272: L631-L638, 1997 |
| 231. |
McMahon TJ,
Hood JS,
Bellan JA, and Kadowitz PJ.
N-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.
J Appl Physiol
71: 2026-2031, 1991 |
| 232. | McQuaid KE, Smyth EM, and Keenan AK. Evidence for modulation of hydrogen peroxide-induced endothelial barrier dysfunction by nitric oxide in vitro. Eur J Pharmacol 307: 233-241, 1996[Web of Science][Medline]. |
| 233. |
McQueston JA,
Cornfield DN,
McMurtry IF, and Abman SH.
Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation.
Am J Physiol Heart Circ Physiol
264: H865-H871, 1993 |
| 234. | Mecham RP, Stenmark KR, and Parks WC. Connective tissue production by vascular smooth muscle in development and disease. Chest 99, Suppl: 43S-47S, 1991. |
| 235. |
Melillo G,
Musso T,
Sica A,
Taylor LS,
Cox GW, and Varesio L.
A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter.
J Exp Med
182: 1683-1693, 1995 |
| 236. |
Melkumyants AM,
Balashov SA, and Khayutin VM.
Control of arterial lumen by shear stress on endothelium.
News Physiol Sci
10: 204-210, 1995 |
| 237. |
Meyer J,
Lentz CW,
Herndon DN,
Nelson S,
Traber LD, and Traber DL.
Effects of halothane anesthesia on vasoconstrictor response to NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, in sheep.
Anesth Analg
77: 1215-1221, 1993 |
| 238. | Moilanen E, Vuorinen P, Kankaanranta H, Metsa-Ketela T, and Vapaatalo H. Inhibition by nitric oxide donors of human polymorphonuclear leucocyte functions. Br J Pharmacol 109: 852-858, 1993[Web of Science][Medline]. |
| 239. | Monboise J-C, Gardes-Albert M, Randoux A, Borel J-P, and Ferradini C. Collagen degradation by superoxide anion in pulse and gamma radiolysis. Biochim Biophys Acta 965: 29-35, 1988[Medline]. |
| 240. | Moncada S, Palmer RMJ, and Higgs EA. Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication. Biochem Pharmacol 38: 1709-1715, 1989[Web of Science][Medline]. |
| 241. |
Moore P,
Velvis H,
Fineman JR,
Soifer SJ, and Heymann MA.
EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.
J Appl Physiol
73: 2151-2157, 1992 |
| 242. | Morgan DM. Polyamines, arginine and nitric oxide. Biochem Soc Trans 22: 879-883, 1994[Web of Science][Medline]. |
| 243. |
Morris SM, and Billiar TR.
New insights into the regulation of inducible nitric oxide synthesis.
Am J Physiol Endocrinol Metab
266: E829-E839, 1994 |
| 244. | Muijsers RBM, Folkerts G, Henricks PA, Sadeghi Hashjin G, and Nijkamp FP. Peroxynitrite: a two-faced metabolite of nitric oxide. Life Sci 60: 1833-1845, 1997[Web of Science][Medline]. |
| 245. |
Mulvany MJ, and Halpern W.
Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats.
Circ Res
41: 19-26, 1977 |
| 246. |
Murad F.
Signal transduction using nitric oxide and cyclic guanosine monophosphate. The 1996 Albert Lasker Medical Research Awards.
JAMA
276: 1189-1192, 1996 |
| 247. |
Muramatsu M,
Rodman DM,
Oka M, and McMurtry IF.
Endothelin-1 mediates nitro-L-arginine vasoconstriction of hypertensive rat lungs.
Am J Physiol Lung Cell Mol Physiol
272: L807-L812, 1997 |
| 248. |
Nakanishi I,
Tajima F,
Nakamura A,
Yagura SY,
Ookawara T,
Yamashita H,
Suzuki K,
Taniguchi N, and Ohno H.
Effects of hypobaric hypoxia on antioxidant enzymes in rats.
J Physiol (Lond)
489: 869-876, 1995 |
| 249. |
Naoki K,
Yamaguchi K,
Suzuki K,
Kudo H,
Nishio K,
Sato N,
Takeshita K,
Suzuki Y, and Tsumura H.
Nitric oxide differentially attenuates microvessel response to hypoxia and hypercapnia in injured lungs.
Am J Physiol Regulatory Integrative Comp Physiol
277: R181-R189, 1999 |
| 250. |
Nathan C, and Xie Q-W.
Regulation of biosynthesis of nitric oxide.
J Biol Chem
269: 13725-13728, 1994 |
| 251. |
Nelin LD, and Dawson CA.
The effect of N-nitro-L-arginine methylester on hypoxic vasoconstriction in the neonatal pig lung.
Pediatr Res
34: 349-353, 1993[Web of Science][Medline].
|
| 252. |
Nelin LD,
Thomas CJ, and Dawson CA.
Effect of hypoxia on nitric oxide production in neonatal pig lung.
Am J Physiol Heart Circ Physiol
271: H8-H14, 1996 |
| 253. | Nelin LS, Dolinski S, Morrisey J, and Dawson C. The effect of inhaled nitric oxide and oxygen on survival of rats in oxygen (Abstract). Am J Respir Crit Care Med 151: A757, 1995. |
| 254. | Newby AC, Southgate KM, and Assender JW. Inhibition of vascular smooth muscle cell proliferation by endothelium-dependent vasodilators. Herz 175: 291-299, 1992. |
| 255. | Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, and Murphy TJ. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 90: 2092-2096, 1992. |
| 256. |
Nishiwaki K,
Nyhan DP,
Rock P,
Desai PM,
Peterson WP,
Pribble CG, and Murray PA.
N-nitro-L-arginine and pulmonary vascular pressure-flow relationship in conscious dogs.
Am J Physiol Heart Circ Physiol
262: H1331-H1337, 1992 |
| 257. | Niwa M, Kawai Y, Nakamura N, and Futaki S. The structure of the promoter region for rat inducible nitric oxide synthase gene. Life Sci 61: 45-49, 1997[Web of Science][Medline]. |
| 258. |
North AJ,
Star RA,
Brannon TS,
Ujiie K,
Wells LB,
Lowenstein CJ,
Snyder SH, and Shaul PW.
Nitric oxide synthase type I and type III gene expression are developmentally regulated in rat lung.
Am J Physiol Lung Cell Mol Physiol
266: L635-L641, 1994 |
| 259. | Novotná J, and Herget J. Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries. Life Sci 62: 1-12, 1998[Web of Science][Medline]. |
| 260. |
Nozaki Y,
Hasegawa Y,
Takeuchi A,
Fan Z-H,
Isobe KI,
Nakashima I, and Shimokata K.
Nitric oxide as an inflammatory mediator of radiation pneumonitis in rats.
Am J Physiol Lung Cell Mol Physiol
272: L651-L658, 1997 |
| 261. | Nunokawa Y, and Tanaka S. Interferon-gamma inhibits proliferation of rat vascular smooth muscle cells by nitric oxide generation. Biochem Biophys Res Commun 188: 409-415, 1992[Web of Science][Medline]. |
| 262. |
O'Connor CM, and Fitzgerald MX.
Matrix metalloproteases and lung disease.
Thorax
49: 602-609, 1994 |
| 263. |
Ogata M,
Ohe M,
Katayose D, and Takishima T.
Modulatory role of EDRF in hypoxic contraction of isolated porcine pulmonary arteries.
Am J Physiol Heart Circ Physiol
262: H691-H697, 1992 |
| 264. | Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, Sakoda T, Kurihara H, Yazaki Y, and Yokoyama M. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 102: 2061-2071, 1998[Web of Science][Medline]. |
| 265. |
Oka M,
Hasunuma K,
Webb SA,
Stelzner TJ,
Rodman DM, and McMurtry IF.
EDRF suppresses an unidentified vasoconstrictor mechanism in hypertensive rat lungs.
Am J Physiol Lung Cell Mol Physiol
264: L587-L597, 1993 |
| 266. | Okamoto T, Akaike T, Nagano T, Miyajima S, Suga M, Ando M, Ichimori K, and Maeda H. Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: a novel mechanism for procollagenase activation involving nitric oxide. Arch Biochem Biophys 342: 261-274, 1997[Web of Science][Medline]. |
| 267. | Okamoto T, Akaike T, Suga M, Maeda H, and Ando M. Involvement of glutathione in activation of human matrix metalloproteinases by peroxynitrite: a novel function of glutathione in oxidative tissue injury (Abstract). Am J Respir Crit Care Med 155: A187, 1997. |
| 268. |
Orton EC,
Reeves JT, and Stenmark KR.
Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension.
J Appl Physiol
65: 2459-2467, 1988 |
| 269. | Owens MW, Milligan SA, and Grisham MB. Inhibition of pleural mesothelial cell collagen synthesis by nitric oxide. Free Radical Biol Med 21: 601-607, 1996[Web of Science][Medline]. |
| 270. |
Ozaki M,
Marshall C,
Amaki Y, and Marshall BE.
Role of wall tension in hypoxic responses of isolated rat pulmonary arteries.
Am J Physiol Lung Cell Mol Physiol
275: L1069-L1077, 1998 |
| 271. |
Paky A,
Michael JR,
Burke Wolin TM,
Wolin MS, and Gurtner GH.
Endogenous production of superoxide by rabbit lungs: effects of hypoxia or metabolic inhibitors.
J Appl Physiol
74: 2868-2874, 1993 |
| 272. |
Palmer LA,
Semenza GL,
Stoler MH, and Johns RA.
Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1.
Am J Physiol Lung Cell Mol Physiol
274: L212-L219, 1998 |
| 273. | Papapetropoulos A, Garcia-Cardena G, Madri JA, and Sessa WC. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 100: 3131-3139, 1997[Web of Science][Medline]. |
| 274. |
Parenti A,
Morbidelli L,
Cui XL,
Douglas JG,
Hood JD,
Granger HJ,
Ledda F, and Ziche M.
Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium.
J Biol Chem
273: 4220-4226, 1998 |
| 275. |
Peacock A.
Vasodilators in pulmonary hypertension.
Thorax
48: 1196-1199, 1993 |
| 276. | Peacock AJ. The role of vasodilators in treating pulmonary hypertension secondary to hypoxic lung disease. In: Pulmonary Circulation: A Handbook for Clinicians, edited by Peacock AJ. London: Chapman & Hall, 1996, p. 195-209. |
| 277. |
Perreault T, and De Marte J.
Maturational changes in endothelium-derived relaxations in newborn piglet pulmonary circulation.
Am J Physiol Heart Circ Physiol
264: H302-H309, 1993 |
| 278. |
Perrella MA,
Edell ES,
Krowka MJ,
Cortese DA, and Burnett JC.
Endothelium-derived relaxing factor in pulmonary and renal circulations during hypoxia.
Am J Physiol Regulatory Integrative Comp Physiol
263: R45-R50, 1992 |
| 279. |
Perrella MA,
Hildebrand FL,
Margulies KB, and Burnett JC.
Endothelium-derived relaxing factor in regulation of basal cardiopulmonary and renal function.
Am J Physiol Regulatory Integrative Comp Physiol
261: R323-R328, 1991 |
| 280. | Persson MG, Gustafsson LE, Wiklund NP, Moncada S, and Hedqvist P. Endogenous nitric oxide as a probable modulator of pulmonary circulation and hypoxic pressor response in vivo. Acta Physiol Scand 140: 449-457, 1990[Web of Science][Medline]. |
| 281. | Persson MG, Kalzén H, and Gustafsson LE. Oxygen or low concentrations of nitric oxide reverse pulmonary vasoconstriction induced by nitric oxide synthesis inhibition in rabbits. Acta Physiol Scand 150: 405-411, 1994[Web of Science][Medline]. |
| 282. | Peterson DA, Peterson DC, Archer S, and Weir EK. The nonspecificity of specific nitric oxide synthase inhibitors. Biochem Biophys Res Commun 187: 797-801, 1992[Web of Science][Medline]. |
| 283. | Pierce MR, Voelker CA, Sosenko IRS, Bustamante S, Olister SM, Zhang XJ, Clark DA, and Miller MJS. Nitric oxide synthase inhibition decreases tolerance to hyperoxia in newborn rats. Mediat Inflamm 4: 431-436, 1995. |
| 284. |
Poiani GJ,
Tozzi CA,
Yohn SA,
Pierce RA,
Belsky SA,
Berg RA,
Yu SY,
Deak SB, and Riley DJ.
Collagen and elastin metabolism in hypertensive pulmonary arteries of rats.
Circ Res
66: 968-978, 1990 |
| 285. |
Pollman MJ,
Hall JL, and Gibbons GH.
Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury: influence of redox state and cell phenotype.
Circ Res
84: 113-121, 1999 |
| 286. |
Pollman MJ,
Yamada T,
Horiuchi M, and Gibbons GH.
Vasoactive substances regulate vascular smooth muscle cell apoptosis: countervailing influences of nitric oxide and angiotensin II.
Circ. Res
79: 748-756, 1996 |
| 287. | Pollock DM, Keith TL, and Highsmith RF. Endothelin receptors and calcium signaling. FASEB J 9: 1196-1204, 1995[Abstract]. |
| 288. | Pracyk JB, Tanaka K, Hegland DD, Kim KS, Sethi R, Rovira, Blazina DR, Lee L, Bruder JT, Kovesdi I, Goldshmidt-Clermont PJ, Irani K, and Finkel T. A requirement for the rac1 GTPase in the signal transduction pathway leading to cardiac myocyte hypertrophy. J Clin Invest 102: 929-937, 1998[Web of Science][Medline]. |
| 289. | Rabinovitch M. Pulmonary hypertension in presence of high blood flow. In: The Pulmonary Circulation in Health and Disease, edited by Will JA, Dawson CA, Weir EK, and Buckner CK. Orlando, FL: Academic, 1987, p. 423-442. |
| 290. |
Rabinovitch M.
Pulmonary hypertension: updating a mysterious disease.
Cardiovasc Res
34: 268-272, 1997 |
| 291. | Rairigh RL, Le Cras TD, Ivy DD, Kinsella JP, Richter G, Horan MP, Fan ID, and Abman SH. Role of inducible nitric oxide synthase in regulation of pulmonary vascular tone in the late gestation ovine fetus. J Clin Invest 101: 15-21, 1998[Web of Science][Medline]. |
| 292. | Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, and Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro: implications for atherosclerotic plaque stability. J Clin Invest 98: 2572-2579, 1996[Web of Science][Medline]. |
| 293. |
Ranjan V,
Xiao Z, and Diamond SL.
Constitutive NOS expression in cultured endothelial cells is elevated by fluid shear stress.
Am J Physiol Heart Circ Physiol
269: H550-H555, 1995 |
| 294. |
Rees DD,
Palmer RMJ, and Moncada S.
Role of endothelium-derived nitric oxide in the regulation of blood pressure.
Proc Natl Acad Sci USA
86: 3375-3378, 1989 |
| 295. | Reeves JT, and Groves BM. Approach to the patient with pulmonary hypertension. In: Pulmonary Hypertension, edited by Weir EK, and Reeves JT. Mount Kisco, NY: Futura, 1984, p. 1-44. |
| 296. | Reeves JT, and Herget J. Experimental models of pulmonary hypertension. In: Pulmonary Hypertension, edited by Weir EK, and Reeves JT. Mount Kisco, NY: Futura, 1984, p. 361-391. |
| 297. |
Reid LM.
Structure and function in pulmonary hypertension: new perceptions.
Chest
89: 279-288, 1986 |
| 298. | Reid LM. Structural remodeling of the pulmonary vasculature by environmental change and disease. In: The Pulmonary Circulation and Gas Exchange, edited by Wagner WW, and Weir EK. Mount Kisco, NY: Futura, 1994, p. 77-110. |
| 299. |
Rengasamy A, and Johns RA.
Determination of Km for oxygen of nitric oxide synthase isoforms.
J Pharmacol Exp Ther
276: 30-33, 1996 |
| 300. |
Resta TC,
Chicoine LG,
Omdahl JL, and Walker BR.
Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia.
Am J Physiol Heart Circ Physiol
276: H699-H708, 1999 |
| 301. |
Resta TC,
Gonzales RJ,
Dail WG,
Sanders TC, and Walker BR.
Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension.
Am J Physiol Heart Circ Physiol
272: H806-H813, 1997 |
| 302. |
Resta TC,
O'Donaughy TL,
Earley S,
Chicoine LG, and Walker BR.
Unaltered vasoconstrictor responsiveness after iNOS inhibition in lungs from chronically hypoxic rats.
Am J Physiol Lung Cell Mol Physiol
276: L122-L130, 1999 |
| 303. |
Resta TC, and Walker BR.
Orally administered L-arginine does not alter right ventricular hypertrophy in chronically hypoxic rats.
Am J Physiol Regulatory Integrative Comp Physiol
266: R559-R563, 1994 |
| 304. |
Resta TC, and Walker BR.
Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation.
Am J Physiol Heart Circ Physiol
270: H888-H896, 1996 |
| 305. | Richardson JB. Innervation of the pulmonary circulation: an overview. In: The Pulmonary Circulation in Health and Disease, edited by Will JA, Dawson CA, Weir EK, and Buckner CK. Orlando, FL: Academic, 1987, p. 9-14. |
| 306. |
Robbins CG,
Horowitz S,
Merritt TA,
Kheiter A,
Tierney J,
Narula P, and Davis JM.
Recombinant human superoxide dismutase reduces lung injury caused by inhaled nitric oxide and hyperoxia.
Am J Physiol Lung Cell Mol Physiol
272: L903-L907, 1997 |
| 307. | Roberts JD, Kinsella JP, and Abman SH. Inhaled nitric oxide in neonatal pulmonary hypertension and severe respiratory distress syndrome: experimental and clinical studies. In: Nitric Oxide and the Lung, edited by Zapol WM, and Bloch KD. New York: Dekker, 1997, p. 333-363. |
| 308. |
Roberts JD,
Roberts CT,
Jones RC,
Zapol WM, and Bloch KD.
Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat.
Circ Res
76: 215-222, 1995 |
| 309. | Robertson BE, Warren JB, and Nye PCG. Inhibition of nitric oxide synthesis potentiates hypoxic vasoconstriction in isolated rat lungs. Exp Physiol 75: 255-257, 1990[Abstract]. |
| 310. |
Rodman DM.
Chronic hypoxia selectively augments rat pulmonary artery Ca2+ and K+ channel-mediated relaxation.
Am J Physiol Lung Cell Mol Physiol
263: L88-L94, 1992 |
| 311. |
Roos CM,
Frank DU,
Xue C,
Johns RA, and Rich GF.
Chronic inhaled nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats.
J Appl Physiol
80: 252-260, 1996 |
| 312. | Rubanyi GM, Ho EH, Cantor EH, Lumma WC, and Botelho LHP. Cytoprotective function of nitric oxide: inactivation of superoxide radicals from human leukocytes. Biochem Biophys Res Commun 181: 1392-1397, 1991[Web of Science][Medline]. |
| 313. | Rubbo H, Darley-Usmar V, and Freeman BA. Nitric oxide regulation of tissue free radical injury. Chem Res Toxicol 9: 809-820, 1996[Web of Science][Medline]. |
| 314. |
Rubbo H,
Radi R,
Trujillo M,
Teller R,
Kalyanaraman B,
Barnes S,
Kirk M, and Freeman BA.
Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation.
J Biol Chem
269: 26066-26075, 1994 |
| 315. |
Rubin LJ.
Primary pulmonary hypertension.
Chest
104: 236-250, 1993 |
| 316. | Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, and Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101: 731-736, 1998[Web of Science][Medline]. |
| 317. |
Rudolph AM,
Kurland MD,
Auld PAM, and Paul MH.
Effects of vasodilator drugs on normal and serotonin-constricted pulmonary vessels of the dog.
Am J Physiol
197: 617-623, 1959 |
| 318. |
Russ RD, and Walker BR.
Maintained endothelium-dependent pulmonary vasodilation following chronic hypoxia in the rat.
J Appl Physiol
74: 339-344, 1993 |
| 319. | Russell P, Wright C, Kapeller K, Barer G, and Howard P. Attenuation of chronic hypoxic pulmonary hypertension in rats by cyclooxygenase products and by nitric oxide. Eur Respir J 6: 1501-1506, 1993[Abstract]. |
| 320. | Ryan US, and Vann JM. Endothelial cells: a source and target of oxidant damage. In: Oxygen Radicals in Biology and Medicine, edited by Simic MG, Taylor KA, Ward JF, and von Sonntag C. New York: Plenum, 1988, p. 963-968. |
| 321. |
Ryrfeldt A,
Bannenberg G, and Moldenus P.
Free radicals and lung disease.
Brit Med Bull
49: 588-603, 1993 |
| 322. |
Salameh G,
Karamsetty MR,
Warburton RR,
Klinger JR,
Ou LC, and Hill NS.
Differences in acute hypoxic pulmonary vasoresponsiveness between rat strains: role of endothelium.
J Appl Physiol
87: 356-362, 1999 |
| 323. | Salceda S, Beck I, Srinivas V, and Caro J. Complex role of protein phosphorylation in gene activation by hypoxia. Kidney Int 51: 556-559, 1997[Web of Science][Medline]. |
| 324. | Salvaterra CG, and Rubin LJ. Investigation and management of pulmonary hypertension in chronic obstructive pulmonary disease. Am Rev Respir Dis 148: 1414-1417, 1993[Web of Science][Medline]. |
| 325. |
Sato K,
Rodman DM, and McMurtry IF.
Hypoxia inhibits increased ETB receptor-mediated NO synthesis in hypertensive rat lungs.
Am J Physiol Lung Cell Mol Physiol
276: L571-L581, 1999 |
| 326. | Sato K, Webb S, Tucker A, Rabinovitch M, O'Brien R, McMurtry IF, and Stelzner TJ. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis 145: 793-797, 1992[Web of Science][Medline]. |
| 327. |
Scarborough JE,
Daggett CW,
Lodge AJ,
Chai PJ,
Williamson JA,
Jaggers J,
George SE, and Ungerleider RM.
The role of endothelial nitric oxide synthase expression in the development of pulmonary hypertension in chronically hypoxic infant swine.
J Thorac Cardiovasc Surg
115: 343-348, 1998 |
| 328. | Schaffer MR, Efron PA, Thornton FJ, Klingel K, Gross SS, and Barbul A. Nitric oxide, an autocrine regulator of wound fibroblast synthetic function. J Immunol 158: 2375-2381, 1997[Abstract]. |
| 329. | Schmidt HHW, Lohmann SM, and Walter U. The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta 1178: 153-175, 1993[Medline]. |
| 330. | Scott PH, Belham CM, Peacock AJ, and Plevin R. Intracellular signalling pathways that regulate vascular cell proliferation: effect of hypoxia. Exp Physiol 82: 317-326, 1997[Web of Science][Medline]. |
| 331. |
Scott-Burden T.
Extracellular matrix: the cellular environment.
News Physiol Sci
9: 110-115, 1994 |
| 332. | Seki J, Nishio M, Kato Y, Motoyama Y, and Yoshida K. FK409, a new nitric oxide donor, suppresses smooth muscle proliferation in the rat model of balloon angioplasty. Atherosclerosis 117: 97-106, 1996[Web of Science]. |
| 333. |
Semenza GL, and Wang GL.
A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.
Mol Cell Biol
12: 5447-5454, 1992 |
| 334. |
Serraf A,
Herve P,
Labat C,
Mazmanian G-M,
de Montpreville V,
Planche C, and Brink C.
Endothelial dysfunction in venous pulmonary hypertension in the neonatal piglet.
Ann Thorac Surg
59: 1155-1161, 1995 |
| 335. |
Sessa WC,
Pritchard K,
Seyedi N,
Wang J, and Hintze TH.
Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression.
Circ Res
74: 349-353, 1994 |
| 336. | Settergren G, Angdin M, Astudillo R, Gelinder S, Liska J, Lundberg JO, and Weitzberg E. Decreased pulmonary vascular resistance during nasal breathing: modulation by endogenous nitric oxide from the paranasal sinuses. Acta Physiol Scand 163: 235-239, 1998[Web of Science][Medline]. |
| 337. |
Sharma RV,
Tan E,
Fang S,
Gurjar MV, and Bhalla RC.
NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells.
Am J Physiol Heart Circ Physiol
276: H1450-H1459, 1999 |
| 338. | Shaul PW, North AJ, Brannon TS, Ujiie K, Wells LB, Nisen PA, Lowenstein CJ, Snyder SH, and Star RA. Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Respir Cell Mol Biol 13: 167-174, 1995[Abstract]. |
| 339. | Shaul PW, Wells LB, and Horning KM. Acute and prolonged hypoxia attenuate endothelial nitric oxide production in rat pulmonary arteries by different mechanisms. J Cardiovasc Pharmacol 22: 819-827, 1993[Web of Science][Medline]. |
| 340. |
Sherman TS,
Chen Z,
Yuhanna IS,
Lau KS,
Margraf LR, and Shaul PW.
Nitric oxide synthase isoform expression in the developing lung epithelium.
Am J Physiol Lung Cell Mol Physiol
276: L383-L390, 1999 |
| 341. | Sjostrom K, and Crapo JD. Structural and biochemical adaptive changes in rat lung after exposure to hypoxia. Lab Invest 48: 68-79, 1983[Web of Science][Medline]. |
| 342. | Smith LJ, and Anderson J. Oxygen-induced lung damage. Am Rev Respir Dis 146: 1452-1457, 1992[Web of Science][Medline]. |
| 343. |
Sobin SS,
Tremer HM,
Hardy JD, and Chiodi HP.
Changes in arteriole in acute and chronic hypoxic, pulmonary hypertension and recovery rat.
J Appl Physiol
55: 1445-1455, 1983 |
| 344. | Soff GA, Cornwell TL, Cundiff DL, Gately S, and Lincoln TM. Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP. J Clin Invest 100: 2580-2587, 1997[Web of Science][Medline]. |
| 345. |
Sogawa K,
Numayama-Tsuruta K,
Ema M,
Abe M,
Abe H, and Fujii-Kuriyama Y.
Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia.
Proc Natl Acad Sci USA
95: 7368-7373, 1998 |
| 346. |
Sprague RS,
Ellsworth ML,
Stephenson AH, and Lonigro AJ.
ATP: the red blood cell link to NO and local control of the pulmonary circulation.
Am J Physiol Heart Circ Physiol
271: H2717-H2722, 1996 |
| 347. |
Sprague RS,
Thiemermann C, and Vane JR.
Endogenous endothelium-derived relaxing factor opposes hypoxic pulmonary vasoconstriction and supports blood flow to hypoxic alveoli in anesthetized rabbits.
Proc Natl Acad Sci USA
89: 8711-8715, 1992 |
| 348. |
Stamler JS,
Loh E,
Roddy M-A,
Currie KE, and Creager MA.
Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.
Circulation
89: 2035-2040, 1994 |
| 349. | Steeds RP, Thompson JS, Channer KS, and Morice AH. Response of normoxic pulmonary arteries of the rat in the resting and contracted state to NO synthase blockade. Br J Pharmacol 122: 99-102, 1997[Web of Science][Medline]. |
| 350. | Steinhorn RH, Morin FC, and Fineman JR. Models of persistent pulmonary hypertension of the newborn (PPHN) and the role of cyclic guanosine monophosphate (GMP) in pulmonary vasorelaxation. Semin Perinatol 21: 393-408, 1997[Web of Science][Medline]. |
| 351. | Stelzner TJ, O'Brien RF, Sato K, and Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats: modulation by glucocorticoids. J Clin Invest 82: 1840-1847, 1988. |
| 352. |
Stelzner TJ,
O'Brien RF,
Yanagisawa M,
Sakurai T,
Sato K,
Webb S,
Zamora M,
McMurtry IF, and Fisher JH.
Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol
262: L614-L620, 1992 |
| 353. | Stenmark KR, and Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 59: 89-144, 1997[Web of Science][Medline]. |
| 354. |
Steudel W,
Ichinose F,
Huang PL,
Hurford WE,
Jones RC,
Bevan JA,
Fishman MC, and Zapol WM.
Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene.
Circ Res
81: 34-41, 1997 |
| 355. | Steudel W, Scherrer-Crosbie M, Bloch KD, Weimann J, Huang PL, Jones RC, Picard MH, and Zapol WM. Sustained pulmonary hypertension and right ventricular hypertrophy after chronic hypoxia in mice with congenital deficiency of nitric oxide synthase 3. J Clin Invest 101: 2468-2477, 1998[Web of Science][Medline]. |
| 356. | Stuehr DJ. Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol 37: 339-359, 1997[Web of Science][Medline]. |
| 357. |
Sugita T,
Hyers TM,
Daubner IM,
Wagner WW,
McMurtry IF, and Reeves JT.
Lung vessel leak preceedes right ventricular hypertrophy in monocrotaline-treated rats.
J Appl Physiol
54: 371-374, 1983 |
| 358. |
Sutton JR,
Reeves JT,
Wagner PD,
Groves BM,
Cymerman A,
Malconian MK,
Rock PB,
Young PM,
Walter SD, and Houston CS.
Operation Everest II: oxygen transport during exercise at extreme simulated altitude.
J Appl Physiol
64: 1309-1321, 1988 |
| 359. |
Suzuki K,
Naoki K,
Kudo H,
Nishio K,
Sato N,
Aoki T,
Suzuki Y,
Takeshita K,
Miyata A,
Tsumura H,
Yamakawa Y, and Yamaguchi K.
Impaired hypoxic vasoconstriction in intra-acinar microvasculature in hyperoxia-exposed rat lungs.
Am J Respir Crit Care Med
158: 602-609, 1998 |
| 360. | Szabo C. The pathological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. Shock 6: 79-88, 1996[Medline]. |
| 361. |
Takaya J,
Teraguchi M,
Nogi S,
Ikemoto Y, and Kobayashi Y.
Relation between plasma nitrate and mean pulmonary arterial pressure in ventricular septal defect.
Arch Dis Child
79: 498-501, 1998 |
| 362. | Tamayo L, López-López JR, Castañeda J, and González C. Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism. Pflügers Arch 434: 698-704, 1997[Web of Science][Medline]. |
| 363. |
Teng GQ, and Barer GR.
In vitro responses of lung arteries to acute hypoxia after NO synthase blockade or chronic hypoxia.
J Appl Physiol
79: 763-770, 1995 |
| 364. |
Tiktinsky MH, and Morin FC.
Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor.
Am J Physiol Heart Circ Physiol
265: H376-H380, 1993 |
| 365. | Todorovich-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, and Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis 146: 213-223, 1992[Web of Science][Medline]. |
| 366. | Tomado RP, Brandt H, Meddelin H, and Doria J. Vascular lesions in experimental pulmonary embolism. Am Heart J 61: 515-524, 1961[Web of Science][Medline]. |
| 367. |
Topper JN,
Cai J,
Falb D, and Gimbrone MA.
Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress.
Proc Natl Acad Sci USA
93: 10417-10422, 1996 |
| 368. | Torok B, Roth E, Zsoldos T, Tigyi A, Matkovics B, and Szabo L. Lipid peroxidation in lungs of rats exposed to hyperoxic, hypoxic and ischemic effects. Exp Pathol 20: 221-226, 1986. |
| 369. | Trachtman H, Futterweit S, Crag P, Reddy P, and Singhal PC. Nitric oxide stimulates activity of 72-kDa neutral matrix metalloproteinase in cultured mesangial cells. Biochem Biophys Res Commun 218: 704-708, 1996[Web of Science][Medline]. |
| 370. | Trachtman H, Futterweit S, and Singhal P. Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured mesangial cells. Biochem Biophys Res Commun 207: 120-125, 1995[Web of Science][Medline]. |
| 371. |
Tseng C-M,
Goodman LW,
Rubin LJ, and Tod ML.
NG-monomethyl-L-arginine paradoxically relaxes preconstricted canine intrapulmonary arteries.
J Appl Physiol
74: 549-558, 1993 |
| 372. |
Tuder RM,
Cool CD,
Geraci MW,
Wang J,
Abman SH,
Wright L,
Badesch D, and Voelkel NF.
Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension.
Am J Respir Crit Care Med
159: 1925-1932, 1999 |
| 373. | Tuohy MB, Bain MH, and Greening AP. Rat alveolar function is primed by exposure to hypoxia (Abstract). Eur Respir J 6: 267S, 1993. |
| 374. |
Twort CHC, and van Breemen C.
Cyclic guanosine monophosphate-enhanced sequestration of Ca2+ by sarcoplasmic reticulum in vascular smooth muscle.
Circ Res
62: 961-964, 1988 |
| 375. |
Tyler RC,
Muramatsu M,
Abman SH,
Stelzner TJ,
Rodman DM,
Bloch KD, and McMurtry IF.
Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol
276: L297-L303, 1999 |
| 376. | Uncles DR, Daugherty MO, Frank DU, Roos CM, and Rich GF. Nitric oxide modulation of pulmonary vascular resistance is red blood cell dependent in isolated rat lungs. Anesth Analg 83: 1212-1217, 1996[Abstract]. |
| 377. | Vallance P, Collier J, and Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 8670: 997-1000, 1989. |
| 378. | Vallance P, Leone A, Calver A, Collier J, and Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339: 572-575, 1992[Web of Science][Medline]. |
| 379. | Vandeplassche G, Hermans C, Thoné F, and Borgers M. Mitochondrial hydrogen peroxide generation by NADH-oxidase activity following regional myocardial ischemia in the dog. J Mol Cell Cardiol 21: 383-392, 1989[Web of Science][Medline]. |
| 380. | van Gelderen EM, Den Boer MO, and Saxena PR. NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig. Naunyn-Schmiedebergs Arch Pharmacol 348: 417-423, 1993[Web of Science][Medline]. |
| 381. | Vanhoutte PM. Other endothelium-derived vasoactive factors. Circulation 87: V-9-V-17, 1993. |
| 382. |
Vender RL.
Chronic hypoxic pulmonary hypertension: cell biology to pathophysiology.
Chest
106: 236-243, 1994 |
| 383. |
Vijay P,
Szekely L,
Sharp TG,
Miller A,
Bando K, and Brown JW.
Adrenomedullin in patients at high risk for pulmonary hypertension.
Ann Thorac Surg
66: 500-505, 1998 |
| 384. | Vogel JHK, Cameron D, and Jamieson G. Chronic pharmacologic treatment of experimental hypoxic pulmonary hypertension. With observations on rate of change in pulmonary arterial pressure. Am Heart J 72: 50-59, 1966[Web of Science][Medline]. |
| 385. |
von der Leyen HE,
Gibbons GH,
Morishita R,
Lewis NP,
Zhang L,
Nakajima M,
Kaneda Y,
Cooke JP, and Dzau VJ.
Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene.
Proc Natl Acad Sci USA
92: 1137-1141, 1995 |
| 386. | Wagenvoort CA. The pathology of human pulmonary hypertension pattern recognition and specificity. In: The Pulmonary Circulation in Health and Disease, edited by Will JA, Dawson CA, Weir EK, and Buckner CK. Orlando, FL: Academic, 1987, p. 15-25. |
| 387. |
Wang GL,
Jiang BH,
Rue EA, and Semenza GL.
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
Proc Natl Acad Sci USA
92: 5510-5514, 1995 |
| 388. | Wanstall JC, Hughes IE, and O'Donnell SR. Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension. Br J Pharmacol 114: 109-114, 1995[Web of Science][Medline]. |
| 389. | Weir EK, Archer SL, and Rubin LJ. Pulmonary hypertension. In: Cardiovascular Medicine, edited by Willerson JT, and Cohn JN. New York: Churchill Livingstone, 1995, p. 1495-1523. |
| 390. |
Weir EK,
Reeve HL,
Huang JMC,
Michelakis E,
Nelson DP,
Hampl V, and Archer SL.
Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction.
Circulation
94: 2216-2220, 1996 |
| 391. |
Whayne TF, and Severinghaus JW.
Experimental hypoxic pulmonary edema in the rat.
J Appl Physiol
25: 729-732, 1968 |
| 392. | Wiklund NP, Persson MG, Gustafsson LE, Moncada S, and Hedquist P. Modulatory role of endogenous nitric oxide in pulmonary circulation in vivo. Eur J Pharmacol 185: 123-124, 1990[Web of Science][Medline]. |
| 393. | Wilhelm J, Sojková J, and Herget J. Production of hydrogen peroxide by alveolar macrophages from rats exposed to subacute and chronic hypoxia. Physiol Res 45: 185-1991, 1996[Web of Science][Medline]. |
| 394. |
Wilson PS,
Khimenko P,
Moore TM, and Taylor AE.
Perfusate viscosity and hematocrit determine pulmonary vascular responsiveness to NO synthase inhibitors.
Am J Physiol Heart Circ Physiol
270: H1757-H1765, 1996 |
| 395. | Wilson PS, Thompson WJ, Moore TM, Khimenko PL, and Taylor AE. Vasoconstriction increases pulmonary nitric oxide synthesis and circulating cyclic GMP. J Surg Res 70: 75-83, 1997[Web of Science][Medline]. |
| 396. |
Woodman CR,
Muller JM,
Rush JWE,
Laughlin MH, and Price EM.
Flow regulation of ecNOS and Cu/Zn SOD mRNA expression in porcine coronary arterioles.
Am J Physiol Heart Circ Physiol
276: H1058-H1063, 1999 |
| 397. |
Wu X,
Haystead TA,
Nakamoto RK,
Somlyo AV, and Somlyo AP.
Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin: synergism with cyclic nucleotide-activated kinase.
J Biol Chem
273: 11362-11369, 1998 |
| 398. | Wu X, Somlyo AV, and Somlyo AP. Cyclic GMP-dependent stimulation reverses G-protein-coupled inhibition of smooth muscle myosin light chain phosphate. Biochem Biophys Res Commun 220: 658-663, 1996[Web of Science][Medline]. |
| 399. | Xiao Z, Zhang Z, and Diamond SL. Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J Cell Physiol 171: 205-211, 1997[Web of Science][Medline]. |
| 400. | Xu H, and Pearl RG. Effects of L-glutamine on pulmonary hypertension in the perfused rabbit lung. Pharmacology 48: 260-264, 1994[Web of Science][Medline]. |
| 401. |
Xue C, and Johns RA.
Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.
N Engl J Med
333: 1642-1644, 1995 |
| 402. |
Xue C, and Johns RA.
Upregulation of nitric oxide synthase correlates temporally with onset of pulmonary vascular remodeling in the hypoxic rat.
Hypertension
28: 743-753, 1996 |
| 403. |
Xue C,
Rengasamy A,
Le Cras TD,
Koberna PA,
Dailey GC, and Johns RA.
Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia.
Am J Physiol Lung Cell Mol Physiol
267: L667-L678, 1994 |
| 404. |
Xue C,
Reynolds PR, and Johns RA.
Developmental expression of NOS isoforms in fetal rat lung: implications for transitional circulation and pulmonary angiogenesis.
Am J Physiol Lung Cell Mol Physiol
270: L88-L100, 1996 |
| 405. | Yaghi A, Paterson NA, and McCormack DG. Differential effect of nitric oxide synthase inhibitors on acetylcholine-induced relaxation of rat pulmonary and celiac artery rings. Can J Physiol Pharmacol 75: 279-286, 1997[Web of Science][Medline]. |
| 406. |
Yamaguchi K,
Suzuki K,
Naoki K,
Nishio K,
Sato N,
Takeshita K,
Kudo H,
Aoki T,
Suzuki Y,
Miyata A, and Tsumura H.
Response of intra-acinar pulmonary microvessels to hypoxia, hypercapnic acidosis, and isocapnic acidosis.
Circ Res
82: 722-728, 1998 |
| 407. | Yoshida M, Taguchi O, Gabazza EC, Kobayashi T, Yamakami T, Kobayashi H, Maruyama K, and Shima T. Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 155: 526-529, 1997[Abstract]. |
| 408. |
Yu AY,
Frid MG,
Shimoda LA,
Wiener CM,
Stenmark K, and Semenza GL.
Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung.
Am J Physiol Lung Cell Mol Physiol
275: L818-L826, 1998 |
| 409. |
Zelenkov P,
McLoughlin T, and Johns RA.
Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase.
Am J Physiol Lung Cell Mol Physiol
265: L346-L354, 1993 |
| 410. |
Zellers TM,
McCormick J, and Wu Y.
Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins.
Am J Physiol Heart Circ Physiol
267: H139-H147, 1994 |
| 411. |
Zempo N,
Koyama N,
Kenagy RD,
Lea HJ, and Clowes AW.
Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor.
Arterioscler Thromb Vasc Biol
16: 28-33, 1996 |
| 412. |
Zhao L,
Crawley DE,
Hughes JMB,
Evans TW, and Winter RJD.
Endothelium-derived relaxing factor activity in rat lung during hypoxic pulmonary vascular remodeling.
J Appl Physiol
74: 1061-1065, 1993 |
This article has been cited by other articles:
|
|
 |
|
  K. Howell, C. M. Costello, M. Sands, I. Dooley, and P. McLoughlin L-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L1042 - L1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Casey, A. M. Badejo Jr., J. S. Dhaliwal, S. N. Murthy, A. L. Hyman, B. D. Nossaman, and P. J. Kadowitz Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H524 - H533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yin, J. Hoffmann, S. M. Kaestle, N. Neye, L. Wang, J. Baeurle, W. Liedtke, S. Wu, H. Kuppe, A. R. Pries, et al. Negative-Feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-Dependent Regulation of Transient Receptor Potential Vanilloid 4 Circ. Res., April 25, 2008; 102(8): 966 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Jakoubek, J. Bibova, J. Herget, and V. Hampl Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1638 - H1644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. T. Bowen, G. F. Erf, M. E. Chapman, and R. F. Wideman Jr. Plasma Nitric Oxide Concentrations in Broilers After Intravenous Injections of Lipopolysaccharide or Microparticles Poult. Sci., December 1, 2007; 86(12): 2550 - 2554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. V. Evgenov, D. S. Kohane, K. D. Bloch, J.-P. Stasch, G. P. Volpato, E. Bellas, N. V. Evgenov, E. S. Buys, M. J. Gnoth, A. R. Graveline, et al. Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1138 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sharma, A. C. Grobe, D. A. Wiseman, S. Kumar, M. Englaish, I. Najwer, E. Benavidez, P. Oishi, A. Azakie, J. R. Fineman, et al. Lung antioxidant enzymes are regulated by development and increased pulmonary blood flow Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L960 - L971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hodyc, M. Snorek, T. Brtnicky, and J. Herget Respiratory: Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently of nitric oxide production Exp Physiol, September 1, 2007; 92(5): 945 - 951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. J. Suzuki, H. Nagase, C. M. Wong, S. V. Kumar, V. Jain, A.-M. Park, and R. M. Day Regulation of Bcl-xL Expression in Lung Vascular Smooth Muscle Am. J. Respir. Cell Mol. Biol., June 1, 2007; 36(6): 678 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Merkus, B. Houweling, V. J. de Beer, Z. Everon, and D. J. Duncker Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction J. Physiol., May 1, 2007; 580(3): 907 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Abstracts Ann Rheum Dis, March 1, 2007; 66(suppl_1): A6 - A69. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, H. Liu, G. Visner, and B. S. Fletcher Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats FASEB J, December 1, 2006; 20(14): 2594 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. T. Bowen, R. F. Wideman, N. B. Anthony, and G. F. Erf Variation in the Pulmonary Hypertensive Responsiveness of Broilers to Lipopolysaccharide and Innate Variation in Nitric Oxide Production by Mononuclear Cells Poult. Sci., August 1, 2006; 85(8): 1349 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Manukhina, H. F. Downey, and R. T. Mallet Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Experimental Biology and Medicine, April 1, 2006; 231(4): 343 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Hampl, J. Bibova, A. Banasova, J. Uhlik, D. Mikova, O. Hnilickova, V. Lachmanova, and J. Herget Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, January 1, 2006; 290(1): L11 - L20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J.D. Griffiths and T. W. Evans Inhaled Nitric Oxide Therapy in Adults N. Engl. J. Med., December 22, 2005; 353(25): 2683 - 2695. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Murata, K. Kinoshita, M. Hori, M. Kuwahara, H. Tsubone, H. Karaki, and H. Ozaki Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2335 - 2342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Houweling, D. Merkus, M. M. D Dekker, and D. J Duncker Nitric oxide blunts the endothelin-mediated pulmonary vasoconstriction in exercising swine J. Physiol., October 15, 2005; 568(2): 629 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Khoo, L. Zhao, N. J. Alp, J. K. Bendall, T. Nicoli, K. Rockett, M. R. Wilkins, and K. M. Channon Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension Circulation, April 26, 2005; 111(16): 2126 - 2133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Konig, J. Dedio, S. Oess, T. Papadakis, A. Fischer, W. Muller-Esterl, and W. Kummer NOSIP and Its Interacting Protein, eNOS, in the Rat Trachea and Lung J. Histochem. Cytochem., February 1, 2005; 53(2): 155 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Oden and I. M. Cheifetz Neonatal Thyrotoxicosis and Persistent Pulmonary Hypertension Necessitating Extracorporeal Life Support Pediatrics, January 1, 2005; 115(1): e105 - e108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Moreno, G. Gonzalez-Luis, A. Cogolludo, F. Lodi, A. Lopez-Farre, J. Tamargo, E. Villamor, and F. Perez-Vizcaino Soluble guanylyl cyclase during postnatal porcine pulmonary maturation Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L125 - L130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Murata, M. Hori, K. Sakamoto, H. Karaki, and H. Ozaki Dexamethasone Blocks Hypoxia-induced Endothelial Dysfunction in Organ-cultured Pulmonary Arteries Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 647 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. H. Jiang, J. Maruyama, A. Yokochi, M. Iwasaki, H. Amano, Y. Mitani, and K. Maruyama Prolonged Nitric Oxide Inhalation Fails to Regress Hypoxic Vascular Remodeling in Rat Lung Chest, June 1, 2004; 125(6): 2247 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Fike, J. L. Aschner, Y. Zhang, and M. R. Kaplowitz Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn piglets Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1244 - L1254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Kuebler, U. Uhlig, T. Goldmann, G. Schael, A. Kerem, K. Exner, C. Martin, E. Vollmer, and S. Uhlig Stretch Activates Nitric Oxide Production in Pulmonary Vascular Endothelial Cells In Situ Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1391 - 1398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Sauzeau, M. Rolli-Derkinderen, S. Lehoux, G. Loirand, and P. Pacaud Sildenafil Prevents Change in RhoA Expression Induced by Chronic Hypoxia in Rat Pulmonary Artery Circ. Res., October 3, 2003; 93(7): 630 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Millatt, G. StJ. Whitley, D. Li, J. M. Leiper, H. M. Siragy, R. M. Carey, and R. A. Johns Evidence for Dysregulation of Dimethylarginine Dimethylaminohydrolase I in Chronic Hypoxia-Induced Pulmonary Hypertension Circulation, September 23, 2003; 108(12): 1493 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Girgis, D. Li, X. Zhan, J. G. N. Garcia, R. M. Tuder, P. M. Hassoun, and R. A. Johns Attenuation of chronic hypoxic pulmonary hypertension by simvastatin Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H938 - H945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Herget, J. Novotna, J. Bibova, V. Povysilova, M. Vankova, and V. Hampl Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L199 - L208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Murata, K. Sato, M. Hori, H. Ozaki, and H. Karaki Decreased Endothelial Nitric-oxide Synthase (eNOS) Activity Resulting from Abnormal Interaction between eNOS and Its Regulatory Proteins in Hypoxia-induced Pulmonary Hypertension J. Biol. Chem., November 8, 2002; 277(46): 44085 - 44092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Droma, M. Hanaoka, M. Ota, Y. Katsuyama, T. Koizumi, K. Fujimoto, T. Kobayashi, and K. Kubo Positive Association of the Endothelial Nitric Oxide Synthase Gene Polymorphisms With High-Altitude Pulmonary Edema Circulation, August 13, 2002; 106(7): 826 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.H. Jiang, J. Maruyama, A. Yokochi, H. Amano, Y. Mitani, and K. Maruyama Correlation of inhaled nitric-oxide induced reduction of pulmonary artery pressure and vascular changes Eur. Respir. J., July 1, 2002; 20(1): 52 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. Chicoine, J. W. Avitia, C. Deen, L. D. Nelin, S. Earley, and B. R. Walker Developmental differences in pulmonary eNOS expression in response to chronic hypoxia in the rat J Appl Physiol, July 1, 2002; 93(1): 311 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Zhang, B. Molino, L. Yan, T. Haim, Y. Vaks, P. M. Scholz, and H. R. Weiss Nitric oxide and cGMP protein kinase activity in aged ventricular myocytes Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2304 - H2309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kanno, Y.-J. L. Wu, P. C. Lee, T. R. Billiar, and C. Ho Angiotensin-Converting Enzyme Inhibitor Preserves p21 and Endothelial Nitric Oxide Synthase Expression in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats Circulation, August 21, 2001; 104(8): 945 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Le Cras and I. F. McMurtry Nitric oxide production in the hypoxic lung Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L575 - L582. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
P < 0.01. [Data from Stamler et al.
(
80 µm) pulmonary arteries. [Data
from Xue et al. (