title: Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats.
abstract: Recent studies have shown that the long-term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin-II (AngII)-dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hypertension was induced by 10 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP-lowering effects of sEH inhibition in I3C-induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced rats elicited dose-dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP-lowering effect of sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin-angiotensin system activity. Long-term antihypertensive action of cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy) benzoic acid in I3C-induced Cyp1a1-Ren-2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sporková
authors.forename: Sárka
authors.initials: S
authors.lastname: Jíchová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Sung H
authors.initials: SH
authors.lastname: Hwang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kompanowska-Jezierska
authors.forename: Janusz
authors.initials: J
authors.lastname: Sadowski
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: Luděk
authors.initials: L
authors.lastname: Cervenka
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D007211:Indoles; C535029:Ren2 protein, rat; D000804:Angiotensin II; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D004851:Epoxide Hydrolases; D012083:Renin
keywords: angiotensin-II; cytochrome P-450 epoxygenase; eicosanoids; epoxyeicosatrienoic acids; hypertension; soluble epoxide hydrolase