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Substituted adamantyl-urea inhibitors of the soluble epoxide hydrolase dilate mesenteric resistance vessels.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Olearczyk, Jeffrey J. Field, Mary B. Kim, In-Hae Morisseau, Christophe H. P. Hammock, Bruce D. Imig, John D. |
| Copyright Year | 2006 |
| 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 F2alpha). 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 microM resulting in a 48 +/- 7% relaxation. Chain-shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 microM, 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. |
| Starting Page | 3013 |
| Ending Page | 3017 |
| Page Count | 5 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://jpet.aspetjournals.org/content/jpet/318/3/1307.full.pdf |
| Alternate Webpage(s) | http://ucanr.edu/sites/hammocklab/files/125677.pdf |
| PubMed reference number | 16772540v1 |
| Volume Number | 318 |
| Issue Number | 3 |
| Journal | The Journal of pharmacology and experimental therapeutics |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-cyclohexyl-3-dodecylurea Amino Acids, Branched-Chain Analog Blood Vessel Blood supply aspects Dilate procedure Dinoprost Epoxy Compounds Epoxyeicosatrienoic Acid Glyburide Hypertensive disease Kidney Diseases Mesenteric Arteries Mesentery Muscle, Smooth, Vascular Omega-3 Fatty Acids Ouabain Palmitoyl-CoA Hydrolase Potassium Chloride Prostaglandins Smooth muscle (tissue) Tetraethylammonium Thioctic Acid Thromboxane A2 Thromboxanes U-44619 dilator epoxide hydrolase activity iberiotoxin incubated urea c-13 |
| Content Type | Text |
| Resource Type | Article |
