Received for publication February 27, 2006.
Revised June 9, 2006.
Accepted for publication June 12, 2006.

Substituted adamantyl-urea inhibitors of the soluble epoxide hydrolase dilate mesenteric resistance vessels

Abstract

The epoxyeicosatrienoic acids (EETs) have been identified as EDHFs. Metabolism of the EETs to the dihydroxyeicosatrienoic acids is catalyzed by the epoxide hydrolase enzyme (sEH). Administration of urea based sEH inhibitors provides protection from hypertension-induced renal injury at least in part by lowering blood pressure. Here, we investigated the hypothesis that a mechanism by which sEH inhibitors elicit their cardiovascular protective effects is via their action on the vasculature. Mesenteric resistance arteries were isolated from Sprague-Dawley rats, pressurized and constricted with U46619. Mesenteric arteries were then incubated with increasing concentrations of the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). AUDA resulted in a concentration-dependent relaxation of mesenteric arteries, with 10 µM resulting in a 48±7% relaxation. Chain shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 µM, the sEH inhibitors CDU, CUDA and 950 were significantly less active resulting in a 25±8%, 10±9% and -8±3% relaxation, respectively. Treatment of mesenteric arteries with tetraethylammonium, iberiotoxin, ouabain or glibenclamide did not alter AUDA-induced relaxation. The AUDA-induced relaxation was completely inhibited when constricted with KCl. In separate experiments, denuding mesenteric resistance vessels did not alter AUDA-induced relaxation. Taken together, these data demonstrate that adamantly-urea inhibitors have unique dilator actions on vascular smooth muscle compared to other sEH inhibitors and that these dilator actions depend on the adamantyl group and carbon chain length.

Key words: cardiovascular, epoxyeicosatrienoic acids, resistance vessels, soluble epoxide hydrolase, vascular reactivity, vascular smooth muscle

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