Abstract
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 F2α). 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 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.
Footnotes
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This work was supported in part by the National Institutes of Health Institutional National Research Service Award Grants 5T32HL066993, HL059699, HL074167, and DK38226; by National Institute of Environmental Health Sciences (NIEHS) Grant ES02710; by NIEHS Superfund Grant ES04699; and by NIEHS Center Grants ES05707 and ESO013933. J.I. is an Established Investigator of the American Heart Association.
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doi:10.1124/jpet.106.103556.
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ABBREVIATIONS: sEH, soluble epoxide hydrolase; EET, epoxyeicosatrienoic acid; AUDA, 12-(3-adamantan-1-yl-ureido)dodecanoic acid; CUDA, 12-(3-cyclohexyl-ureido)dodecanoic acid; AUOA, 8-(3-adamantyl-ureido)-octanoic acid; AUHA, 6-(3-adamantyl-ureido)-hexanoic acid; AUBA, 4-(3-adamantan-1-yl-ureido)butanoic acid; AADU, 1-adamantyl-3-(12-aminododecyl)urea; 950, adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea; DMSO, dimethyl sulfoxide; CDU, 1-cyclohexyl-3-dodecylurea; IbTX, iberiotoxin; MS-PPOH, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; PBS-T, phosphate-buffered saline containing 0.1% Tween 20; TEA, tetraethylammonium; DMF, dimethyl formamide; E-64, trans-epoxysuccinyl-l-leucylamido(4-guanidino)butane; LC, liquid chromatography; MS, mass spectrometry; TOF, time-of-flight; U46619, 9,11-dideoxy-11,9-epoxymethano-prostaglandin F2α.
- Received February 24, 2006.
- Accepted June 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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