title: Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension.
abstract: In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.
authors.affiliation: Department of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Honetschlägerová
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Husková
authors.forename: Zdeňka
authors.initials: Z
authors.lastname: Vaňourková
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sporková
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Kramer
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Hsing-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Luděk
authors.initials: L
authors.lastname: Červenka
authors.forename: Libor
authors.initials: L
authors.lastname: Kopkan
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017595:Renal Plasma Flow / Q000187:drug effects; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D013997:Time Factors; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000959:Antihypertensive Agents; D001095:Arachidonic Acids; D001565:Benzoates; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; C473112:Ren2 protein, mouse; D000804:Angiotensin II; D014508:Urea; D012964:Sodium; D019363:Cytochrome P-450 CYP1A1; D004851:Epoxide Hydrolases; C529022:EPHX2 protein, rat; D012083:Renin