© 1996 American Heart Association, Inc.
Articles |
Identification of Epoxyeicosatrienoic Acids as Endothelium-Derived Hyperpolarizing Factors
From the Departments of Pharmacology and Toxicology and Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Correspondence to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Abstract Endothelial cells release several
compounds, including prostacyclin, NO, and
endothelium-derived hyperpolarizing factor (EDHF),
that mediate the vascular effects of vasoactive hormones. The identity
of EDHF remains unknown. Since arachidonic acid causes
endothelium-dependent relaxations of
coronary arteries through its metabolism to
epoxyeicosatrienoic acids (EETs) by cytochrome P450,
we wondered if the EETs represent EDHFs. Precontracted bovine
coronary arteries relaxed in an
endothelium-dependent manner to methacholine. The
cytochrome P450 inhibitors, SKF 525A and
miconazole, significantly attenuated these relaxations. They were also
inhibited by tetraethylammonium (TEA), an
inhibitor of Ca2+-activated
K+ channels, and by high
[K+]o
(20 mmol/L). Methacholine also caused
hyperpolarization of coronary smooth muscle
(-27±3.9 versus -40±5.1 mV), which was completely
blocked by SKF
525A and miconazole. In vessels prelabeled with
[3H]arachidonic acid, methacholine
stimulated the release of 6-ketoprostaglandin
F1
, 12-HETE, and the EETs.
Arachidonic acid relaxed precontracted coronary
arteries, which were also blocked by TEA, charybdotoxin, another
Ca2+-activated K+ channel
inhibitor, and high [K+]o.
14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET relaxed precontracted
coronary vessels (EC50, 1x10-6
mol/L). The four regioisomers were equally active. TEA, charybdotoxin,
and high [K+]o attenuated the EET
relaxations. 11,12-EET hyperpolarized coronary smooth muscle
cells from -37±0.2 to -59±0.3 mV. In the
cell-attached mode of
patch clamp, both 14,15-EET and 11,12-EET increased the open-state
probability of a Ca2+-activated K+
channel in coronary smooth muscle cells. This effect was
blocked by TEA and charybdotoxin. These data support the hypothesis
that the EETs are EDHFs.
Key Words: cytochrome P450 • arachidonic acid • K+ channels • smooth muscle • membrane potential
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E. M. Sokoya, A. R. Burns, C. T. Setiawan, H. A. Coleman, H. C. Parkington, and M. Tare Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H385 - H393. [Abstract] [Full Text] [PDF]
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R. H. P. Hilgers, J. Todd Jr., and R. C. Webb Regional heterogeneity in acetylcholine-induced relaxation in rat vascular bed: role of calcium-activated K+ channels Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H216 - H222. [Abstract] [Full Text] [PDF]
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M. A. Carroll, A. B. Doumad, J. Li, M. K. Cheng, J. R. Falck, and J. C. McGiff Adenosine2A receptor vasodilation of rat preglomerular microvessels is mediated by EETs that activate the cAMP/PKA pathway Am J Physiol Renal Physiol, July 1, 2006; 291(1): F155 - F161. [Abstract] [Full Text] [PDF]
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M. Feletou and P. M. Vanhoutte Endothelium-Derived Hyperpolarizing Factor: Where Are We Now? Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1215 - 1225. [Abstract] [Full Text] [PDF]
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 C. R. Lee, K. E. North, M. S. Bray, M. Fornage, J. M. Seubert, J. W. Newman, B. D. Hammock, D. J. Couper, G. Heiss, and D. C. Zeldin Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study Hum. Mol. Genet., May 15, 2006; 15(10): 1640 - 1649. [Abstract] [Full Text] [PDF]
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Z. Yu, V. Y. Ng, P. Su, M. M. Engler, M. B. Engler, Y. Huang, E. Lin, and D. L. Kroetz Induction of Renal Cytochrome P450 Arachidonic Acid Epoxygenase Activity by Dietary {gamma}-Linolenic Acid J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 732 - 738. [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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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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J. Andresen, N. I. Shafi, and R. M. Bryan Jr. Endothelial influences on cerebrovascular tone J Appl Physiol, January 1, 2006; 100(1): 318 - 327. [Abstract] [Full Text] [PDF]
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Y. Liu, A. H. Bubolz, Y. Shi, P. J. Newman, D. K. Newman, and D. D. Gutterman Peroxynitrite reduces the endothelium-derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knockout mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R57 - R65. [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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X. Tang, E. M. Edwards, B. B. Holmes, J. R. Falck, and W. B. Campbell Role of phospholipase C and diacylglyceride lipase pathway in arachidonic acid release and acetylcholine-induced vascular relaxation in rabbit aorta Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H37 - H45. [Abstract] [Full Text] [PDF]
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W. B. Campbell, B. B. Holmes, J. R. Falck, J. H. Capdevila, and K. M. Gauthier Regulation of potassium channels in coronary smooth muscle by adenoviral expression of cytochrome P-450 epoxygenase Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H64 - H71. [Abstract] [Full Text] [PDF]
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M. I. Kotlikoff EDHF Redux: EETs, TRPV4, and Ca2+ Sparks Circ. Res., December 9, 2005; 97(12): 1209 - 1210. [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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 U. R. Michaelis, B. Fisslthaler, E. Barbosa-Sicard, J. R. Falck, I. Fleming, and R. Busse Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis J. Cell Sci., December 1, 2005; 118(23): 5489 - 5498. [Abstract] [Full Text] [PDF]
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D. X. Zhang, K. M. Gauthier, and W. B. Campbell Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1058 - E1063. [Abstract] [Full Text] [PDF]
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Y. Liu, Y. Zhang, K. Schmelzer, T.-S. Lee, X. Fang, Y. Zhu, A. A. Spector, S. Gill, C. Morisseau, B. D. Hammock, et al. The antiinflammatory effect of laminar flow: The role of PPAR{gamma}, epoxyeicosatrienoic acids, and soluble epoxide hydrolase PNAS, November 15, 2005; 102(46): 16747 - 16752. [Abstract] [Full Text] [PDF]
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W. G. Schrage, B. W. Wilkins, V. L. Dean, J. P. Scott, N. K. Henry, M. E. Wylam, and M. J. Joyner Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis J Appl Physiol, November 1, 2005; 99(5): 1866 - 1871. [Abstract] [Full Text] [PDF]
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H. Wang, J. L. Garvin, J. R. Falck, Y. Ren, S. S. Sankey, and O. A. Carretero Glomerular Cytochrome P-450 and Cyclooxygenase Metabolites Regulate Efferent Arteriole Resistance Hypertension, November 1, 2005; 46(5): 1175 - 1179. [Abstract] [Full Text] [PDF]
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J. Vriens, G. Owsianik, B. Fisslthaler, M. Suzuki, A. Janssens, T. Voets, C. Morisseau, B.D. Hammock, I. Fleming, R. Busse, et al. Modulation of the Ca2 Permeable Cation Channel TRPV4 by Cytochrome P450 Epoxygenases in Vascular Endothelium Circ. Res., October 28, 2005; 97(9): 908 - 915. [Abstract] [Full Text] [PDF]
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J. L. Losapio, R. S. Sprague, A. J. Lonigro, and A. H. Stephenson 5,6-EET-induced contraction of intralobar pulmonary arteries depends on the activation of Rho-kinase J Appl Physiol, October 1, 2005; 99(4): 1391 - 1396. [Abstract] [Full Text] [PDF]
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G. J. Gross, J. R. Falck, E. R. Gross, M. Isbell, J. Moore, and K. Nithipatikom Cytochrome P450 and arachidonic acid metabolites: Role in myocardial ischemia/reperfusion injury revisited Cardiovasc Res, October 1, 2005; 68(1): 18 - 25. [Abstract] [Full Text] [PDF]
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J. D. Imig Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases Am J Physiol Renal Physiol, September 1, 2005; 289(3): F496 - F503. [Abstract] [Full Text] [PDF]
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J. M. Seubert, F. Xu, J. P. Graves, J. B. Collins, S. O. Sieber, R. S. Paules, D. L. Kroetz, and D. C. Zeldin Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats Am J Physiol Renal Physiol, September 1, 2005; 289(3): F552 - F561. [Abstract] [Full Text] [PDF]
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