Contributor:

Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic,†Department of Physiology,‡Department of Pha rmacology, Kagawa University, Kagawa, Japan,§Department ofEntomology, UCD Comprehensive Cancer Center, University of California, Davis, CA, USA,¶Department ofPharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA, **Department of Renal and BodyFluid Physiology, M. Mossakowski Medical Research Centre, Polish Academy of Science, Warsaw , Poland,††Section ofNephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany and‡‡Pathophysiology,2nd Faculty of Medicine, Charles University, Prague, Czech Republic

Publisher:

Wiley Publishing

Type of object:

Journal/Article

Abstract:

Recent studies have shown that the long-term antihyper-tensive action of soluble epoxide hydrolase inhibition (sEH)in angiotensin-II (AngII)-dependent hypertension might bemediated by the suppression of intrarenal AngII levels. Totest this hypothesis, we examined the effects of acute(2 days) and chronic (14 days) sEH inhibition on bloodpressure (BP) in transgenic rats with inducible AngII-dependent hypertension. AngII-dependent malignant hyper-tension was induced by 10 days’ dietary administration ofindole-3-carbinol (I3C), a natural xenobiotic that activatesthe mouse renin gene in Cyp1a1-Ren-2 transgenic rats. BPwas monitored by radiotelemetry. Acute and chronic sEHinhibition was achieved using cis-4-(4-(3-adamantan-1-yl-ure-ido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13,26, 60 and 130 mg/L in drinking water. At the end ofexperiments, renal concentrations of epoxyeicosatrienoicacids, their inactive metabolites dihydroxyeicosatrienoicacids and AngII were measured. Acute BP-lowering effectsof sEH inhibition in I3C-induced rats was associated with amarked increase in renal epoxyeicosatrienoic acids to di-hydroxyeicosatrienoic acids ratio and acute natriuresis.Chronic treatment with cis -4-(4-(3-adamantan-1-yl-ureido)cy-clohexyloxy) benzoic acid in I3C-induced rats eliciteddose-dependent persistent BP lowering associated with asignificant reduction of plasma and kidney AngIIlevels. Our findings show that the acute BP-lowering effectof sEH inhibition in I3C-induced Cyp1a1-Ren-2 transgenicrats is mediated by a substantial increase in intrarenal ep-oxyeicosatrienoic acids and their natriuretic action withoutaltering 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 ofintrarenal AngII concentration.

Relation:

Clinical and Experimental Pharmacology and Physiology

Volume:

41

Issue:

12

Start page:

1003

End page:

1013

Detailed Resource Type:

Article

Format:

text/xml

Resource Identifier:

oai:rcin.org.pl:57230

Language:

eng

Language of abstract:

eng

Rights:

Rights Reserved - Restricted Access

Terms of use:

Copyright-protected material. Access only on terminals at the Mossakowski Medical Research Center of the Polish Academy of Sciences, may be used within the limits of statutory user freedoms.

Digitizing institution:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego Polskiej Akademii Nauk

Original in:

Biblioteka Instytutu Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Projects co-financed by:

Program Operacyjny Innowacyjna Gospodarka, lata 2010-2014, Priorytet 2. Infrastruktura strefy B + R

Access:

Closed