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Urea‐based soluble epoxide hydrolase inhibitors dilate mesenteric resistance vessels
Author(s) -
Olearczyk Jeffrey J,
Field Mary B,
Kim InHae,
Morisseau Christophe,
Hammock Bruce D,
Imig John D
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a669-c
Subject(s) - epoxide hydrolase 2 , chemistry , vasodilation , mesenteric arteries , epoxyeicosatrienoic acid , pharmacology , biochemistry , artery , enzyme , medicine , cytochrome p450
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 illicit their cardiovascular protective effects is via their action on the microvasculature. 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 37±7% relaxation. Chain shortened analogs of AUDA had a significantly attenuated vasodilatory response. Interstingly, at 10 μM, the cyclohexyl sEH inhibitors CDU and CUDA were relatively inactive and resulted in a 4±9% and 2±6% relaxation, respectively. Treatment of mesenteric arteries with tetraethylammonium chloride attenuated the AUDA‐induced relaxation, whereas constriction with KCl completely inhibited AUDA‐induced relaxation. Taken together, these data provide support for the hypothesis that AUDA has unique vasodilator actions compared to other sEH inhibitors and that these actions depend on the adamantyl group and carbon chain length.