Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 318, Issue 3, Pages 1307-1314Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.103556
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Funding
- NHLBI NIH HHS [HL059699, 5T32HL066993, HL074167] Funding Source: Medline
- NIDDK NIH HHS [DK38226] Funding Source: Medline
- NIEHS NIH HHS [ES02710, ES04699, ES05707, R37 ES002710, R01 ES013933, ES013933, P30 ES005707, P42 ES004699] Funding Source: Medline
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The epoxyeicosatrienoic acids (EETs) have been identified as endothelium-derived hyperpolarizing factors. Metabolism of the EETs to the dihydroxyeicosatrienoic acids is catalyzed by soluble epoxide hydrolase (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 the thromboxane A2 agonist U46619 (9,11-dideoxy-11,9-epoxymethano- prostaglandin F2 alpha). 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 mu M resulting in a 48 +/- 7% relaxation. Chain-shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 mu M, the sEH inhibitors 1-cyclohexyl-3-dodecylurea, 12-(3-cyclohexylureido) dodecanoic acid, and 950 [adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy) ethoxy] pentyl} urea] 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 adamantyl-urea inhibitors have unique dilator actions on vascular smooth muscle compared with other sEH inhibitors and that these dilator actions depend on the adamantyl group and carbon chain length.
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