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Physiological Reviews, Vol. 82, No. 1, January 2002, pp. 131-185; 10.1152/physrev.00021.2001.
Copyright ©2002 by the American Physiological Society
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Roman, Richard J.
P-450 Metabolites of Arachidonic Acid in the
Control of Cardiovascular Function. Physiol. Rev. 82: 131-185, 2002.
Recent studies have
indicated that arachidonic acid is primarily metabolized by cytochrome
P-450 (CYP) enzymes in the brain, lung, kidney, and
peripheral vasculature to 20-hydroxyeicosatetraenoic acid (20-HETE) and
epoxyeicosatrienoic acids (EETs) and that these compounds play critical
roles in the regulation of renal, pulmonary, and cardiac function and
vascular tone. EETs are endothelium-derived vasodilators that
hyperpolarize vascular smooth muscle (VSM) cells by activating
K+ channels. 20-HETE is a vasoconstrictor produced in VSM
cells that reduces the open-state probability of
Ca2+-activated K+ channels. Inhibitors of the
formation of 20-HETE block the myogenic response of renal, cerebral,
and skeletal muscle arterioles in vitro and autoregulation of renal and
cerebral blood flow in vivo. They also block
tubuloglomerular feedback responses in vivo and the vasoconstrictor
response to elevations in tissue PO2 both in
vivo and in vitro. The formation of 20-HETE in VSM is stimulated by
angiotensin II and endothelin and is inhibited by nitric oxide (NO) and
carbon monoxide (CO). Blockade of the formation of 20-HETE attenuates
the vascular responses to angiotensin II, endothelin, norepinephrine,
NO, and CO. In the kidney, EETs and 20-HETE are produced in the
proximal tubule and the thick ascending loop of Henle. They regulate
Na+ transport in these nephron segments. 20-HETE also
contributes to the mitogenic effects of a variety of growth factors in
VSM, renal epithelial, and mesangial cells. The production of EETs and
20-HETE is altered in experimental and genetic models of hypertension, diabetes, uremia, toxemia of pregnancy, and hepatorenal syndrome. Given
the importance of this pathway in the control of cardiovascular function, it is likely that CYP metabolites of arachidonic acid contribute to the changes in renal function and vascular tone associated with some of these conditions and that drugs that modify the
formation and/or actions of EETs and 20-HETE may have therapeutic benefits.
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A. Gaedigk, D. W. Baker, R. A. Totah, R. Gaedigk, R. E. Pearce, C. A. Vyhlidal, D. C. Zeldin, and J. S. Leeder Variability of CYP2J2 Expression in Human Fetal Tissues J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 523 - 532. [Abstract] [Full Text] [PDF]
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V. Y. Ng, C. Morisseau, J. R. Falck, B. D. Hammock, and D. L. Kroetz Inhibition of Smooth Muscle Proliferation by Urea-Based Alkanoic Acids via Peroxisome Proliferator-Activated Receptor {alpha}-Dependent Repression of Cyclin D1 Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2462 - 2468. [Abstract] [Full Text] [PDF]
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X. Fang, F. M. Faraci, T. L. Kaduce, S. Harmon, M. L. Modrick, S. Hu, S. A. Moore, J. R. Falck, N. L. Weintraub, and A. A. Spector 20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2301 - H2307. [Abstract] [Full Text] [PDF]
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D. F. Alvarez, J. A. King, D. Weber, E. Addison, W. Liedtke, and M. I. Townsley Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier: A Novel Mechanism of Acute Lung Injury Circ. Res., October 27, 2006; 99(9): 988 - 995. [Abstract] [Full Text] [PDF]
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E. Joly, R. Seqqat, B. Flamion, N. Caron, A. Michel, J. D. Imig, and R. Kramp Increased renal vascular reactivity to ANG II after unilateral nephrectomy in the rat involves 20-HETE Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R977 - R986. [Abstract] [Full Text] [PDF]
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F.H. Messerli, G. Mancia, C.R. Conti, A.C. Hewkin, S. Kupfer, A. Champion, R. Kolloch, A. Benetos, C.J. Pepine, K. Nakagawa, et al. Lowering of Blood Pressure--The Lower, the Better?: Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Ann Intern Med 144: 884-893, 2006 J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2345 - 2352. [Full Text] [PDF]
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E. R. Jacobs, D. Zhu, S. Gruenloh, B. Lopez, and M. Medhora VEGF-induced relaxation of pulmonary arteries is mediated by endothelial cytochrome P-450 hydroxylase Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L369 - L377. [Abstract] [Full Text] [PDF]
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T. Lu, D. Ye, X. Wang, J. M. Seubert, J. P. Graves, J. A. Bradbury, D. C. Zeldin, and H.-C. Lee Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms J. Physiol., September 1, 2006; 575(2): 627 - 644. [Abstract] [Full Text] [PDF]
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A. L. Opay, C. R. Mouton, J. J. Mullins, and K. D. Mitchell Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension Am J Physiol Renal Physiol, September 1, 2006; 291(3): F612 - F618. [Abstract] [Full Text] [PDF]
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J. M. Seubert, C. J. Sinal, J. Graves, L. M. DeGraff, J. A. Bradbury, C. R. Lee, K. Goralski, M. A. Carey, A. Luria, J. W. Newman, et al. Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function Circ. Res., August 18, 2006; 99(4): 442 - 450. [Abstract] [Full Text] [PDF]
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S. Diani-Moore, F. Papachristou, E. Labitzke, and A. B. Rifkind INDUCTION OF CYP1A AND CYP2-MEDIATED ARACHIDONIC ACID EPOXYGENATION AND SUPPRESSION OF 20-HYDROXYEICOSATETRAENOIC ACID BY IMIDAZOLE DERIVATIVES INCLUDING THE AROMATASE INHIBITOR VOROZOLE Drug Metab. Dispos., August 1, 2006; 34(8): 1376 - 1385. [Abstract] [Full Text] [PDF]
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A. Dhanasekaran, R. Al-Saghir, B. Lopez, D. Zhu, D. D. Gutterman, E. R. Jacobs, and M. Medhora Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H517 - H531. [Abstract] [Full Text] [PDF]
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R. Inoue, L. J. Jensen, J. Shi, H. Morita, M. Nishida, A. Honda, and Y. Ito Transient Receptor Potential Channels in Cardiovascular Function and Disease Circ. Res., July 21, 2006; 99(2): 119 - 131. [Abstract] [Full Text] [PDF]
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J.-S. Wang, H. Singh, F. Zhang, T. Ishizuka, H. Deng, R. Kemp, M. S. Wolin, T. H. Hintze, N. G. Abraham, A. Nasjletti, et al. Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus Circ. Res., April 14, 2006; 98(7): 962 - 969. [Abstract] [Full Text] [PDF]
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Y. Zhou, H. Huang, H.-H. Chang, J. Du, J. F. Wu, C.-Y. Wang, and M.-H. Wang Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 11 - 18. [Abstract] [Full Text] [PDF]
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M. Guo, R. J. Roman, J. D. Fenstermacher, S. L. Brown, J. R. Falck, A. S. Arbab, P. A. Edwards, and A. G. Scicli 9L Gliosarcoma Cell Proliferation and Tumor Growth in Rats Are Suppressed by N-Hydroxy-N'-(4-butyl-2-methylphenol) Formamidine (HET0016), a Selective Inhibitor of CYP4A J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 97 - 108. [Abstract] [Full Text] [PDF]
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D. Ye, W. Zhou, T. Lu, S. G. Jagadeesh, J. R. Falck, and H.-C. Lee Mechanism of rat mesenteric arterial KATP channel activation by 14,15-epoxyeicosatrienoic acid Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1326 - H1336. [Abstract] [Full Text] [PDF]
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J. Bellien, R. Joannides, M. Iacob, P. Arnaud, and C. Thuillez Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1347 - H1352. [Abstract] [Full Text] [PDF]
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I. Fleming and R. Busse Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function Hypertension, April 1, 2006; 47(4): 629 - 633. [Abstract] [Full Text] [PDF]
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P. Pokreisz, I. Fleming, L. Kiss, E. Barbosa-Sicard, B. Fisslthaler, J. R. Falck, B. D. Hammock, I.-H. Kim, Z. Szelid, P. Vermeersch, et al. Cytochrome P450 Epoxygenase Gene Function in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling Hypertension, April 1, 2006; 47(4): 762 - 770. [Abstract] [Full Text] [PDF]
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 M. R. Metea and E. A. Newman Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J. Neurosci., March 15, 2006; 26(11): 2862 - 2870. [Abstract] [Full Text] [PDF]
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B. T. Larsen, H. Miura, O. A. Hatoum, W. B. Campbell, B. D. Hammock, D. C. Zeldin, J. R. Falck, and D. D. Gutterman Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BKCa channels: implications for soluble epoxide hydrolase inhibition Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H491 - H499. [Abstract] [Full Text] [PDF]
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N. Ben-Amor, P. C. Redondo, A. Bartegi, J. A. Pariente, G. M. Salido, and J. A. Rosado A role for 5,6-epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets J. Physiol., January 15, 2006; 570(2): 309 - 323. [Abstract] [Full Text] [PDF]
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K. Takeuchi, N. Miyata, M. Renic, D. R. Harder, and R. J. Roman Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R84 - R89. [Abstract] [Full Text] [PDF]
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X. Fang, S. Hu, B. Xu, G. D. Snyder, S. Harmon, J. Yao, Y. Liu, B. Sangras, J. R. Falck, N. L. Weintraub, et al. 14,15-Dihydroxyeicosatrienoic acid activates peroxisome proliferator-activated receptor-{alpha} Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H55 - H63. [Abstract] [Full Text] [PDF]
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S. Earley, T. J. Heppner, M. T. Nelson, and J. E. Brayden TRPV4 Forms a Novel Ca2+ Signaling Complex With Ryanodine Receptors and BKCa Channels Circ. Res., December 9, 2005; 97(12): 1270 - 1279. [Abstract] [Full Text] [PDF]
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 L. Wu and R. Wang Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications Pharmacol. Rev., December 1, 2005; 57(4): 585 - 630. [Abstract] [Full Text] [PDF]
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F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2592 - H2601. [Abstract] [Full Text] [PDF]
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A. Sarkis, O. Ito, T. Mori, M. Kohzuki, S. Ito, J. Verbalis, A. W. Cowley Jr., and R. J. Roman Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1333 - F1340. [Abstract] [Full Text] [PDF]
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M. Guo, R. J. Roman, J. R. Falck, P. A. Edwards, and A. G. Scicli Human U251 Glioma Cell Proliferation Is Suppressed by HET0016 [N-Hydroxy-N'-(4-butyl-2-methylphenyl)formamidine], a Selective Inhibitor of CYP4A J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 526 - 533. [Abstract] [Full Text] [PDF]
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