Circulation Research. 2002
Published online before print April 11, 2002, doi: 10.1161/01.RES.0000018162.87285.F8
Published online before print April 11, 2002, doi: 10.1161/01.RES.0000018162.87285.F8
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Submitted on October 19, 2001
Revised on March 7, 2002
Accepted on April 2, 2002
14,15-Epoxyeicosa-5(Z)-Enoic Acid. A Selective Epoxyeicosatrienoic Acid Antagonist That Inhibits Endothelium-Dependent Hyperpolarization and Relaxation in Coronary Arteries
Kathryn M. Gauthier ;
From the Department of Pharmacology and Toxicology (K.M.G., C.D., W.B.C.), Medical College of Wisconsin, Milwaukee, and the Department of Biochemistry (U.M.K., Y.K.R., M.B., J.R.F.), University of Texas Southwestern Medical School, Dallas.
* To whom correspondence should be addressed. E-mail: wbcamp{at}mcw.edu.
Endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle are mediated by endothelium-derived hyperpolarizing factors (EDHFs). EDHF candidates include cytochrome P-450 metabolites of arachidonic acid, K+, hydrogen peroxide, or electrical coupling through gap junctions. In bovine coronary arteries, epoxyeicosatrienoic acids (EETs) appear to function as EDHFs. A 14,15-EET analogue, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) was synthesized and identified as an EET-specific antagonist. In bovine coronary arterial rings preconstricted with U46619, 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET induced concentration-related relaxations. Preincubation of the arterial rings with 14,15-EEZE (10 µmol/L) inhibited the relaxations to 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET but was most effective in inhibiting 14,15-EET--induced relaxations. 14,15-EEZE also inhibited indomethacin-resistant relaxations to methacholine and arachidonic acid and indomethacin-resistant and L-nitroarginine-resistant relaxations to bradykinin. It did not alter relaxation responses to sodium nitroprusside, iloprost, or the K+ channel activators (NS1619 and bimakalim). Additionally, in small bovine coronary arteries pretreated with indomethacin and L-nitroarginine and preconstricted with U46619, 14,15-EEZE (3 µmol/L) inhibited bradykinin (10 nmol/L)--induced smooth muscle hyperpolarizations and relaxations. In rat renal microsomes, 14,15-EEZE (10 µmol/L) did not decrease EET synthesis and did not alter 20-hydroxyeicosatetraenoic acid synthesis. This analogue acts as an EET antagonist by inhibiting the following: (1) EET-induced relaxations, (2) the EDHF component of methacholine-induced, bradykinin-induced, and arachidonic acid--induced relaxations, and (3) the smooth muscle hyperpolarization response to bradykinin. Thus, a distinct molecular structure is required for EET activity, and alteration of this structure modifies agonist and antagonist activity. These findings support a role of EETs as EDHFs.
Key words: epoxyeicosatrienoic acids • arachidonic acid • endothelium-derived hyperpolarizing factors • endothelium • 20-hydroxyeicosatetraenoic acid
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