title: Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system.
abstract: The aim of the present study was to evaluate the hypothesis that the antihypertensive effects of inhibition of soluble epoxide hydrolase (sEH) are mediated by increased intrarenal availability of epoxyeicosatrienoic acids (EETs), with consequent improvement in renal haemodynamic autoregulatory efficiency and the pressure-natriuresis relationship. Ren-2 transgenic rats (TGR), a model of angiotensin (Ang) II-dependent hypertension, and normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats were treated with the sEH inhibitor cis-4-(4-(3-adamantan-1-yl-ureido)cyclohexyloxy)benzoic acid (c-AUCB; 26 mg/L) for 48 h. Then, the effects on blood pressure (BP), autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR), and on the pressure-natriuresis relationship in response to stepwise reductions in renal arterial pressure (RAP) were determined. Treatment with c-AUCB did not significantly change BP, renal autoregulation or pressure-natriuresis in normotensive HanSD rats. In contrast, c-AUCB treatment significantly reduced BP, increased intrarenal bioavailability of EETs and significantly suppressed AngII levels in TGR. However, treatment with c-AUCB did not significantly improve the autoregulatory efficiency of RBF and GFR in response to reductions of RAP and to restore the blunted pressure-natriuresis relationship in TGR. Together, the data indicate that the antihypertensive actions of sEH inhibition in TGR are predominantly mediated via significant suppression of intrarenal renin-angiotensin system activity.
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Sarka
authors.initials: S
authors.lastname: Varcabova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Huskova
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: Sung Hee
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: Kento
authors.initials: K
authors.lastname: Kitada
authors.forename: Ludek
authors.initials: L
authors.lastname: Cervenka
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000959:Antihypertensive Agents; D001565:Benzoates; D014508:Urea; D004851:Epoxide Hydrolases