Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension.
The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyeicosatrienoic acids), on BP (blood pressure) and myocardial infarct size in male heterozygous TGR (Ren-2 renin transgenic rats) with established hypertension. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. Myocardial ischaemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR (assessed as the ratio of EETs to DHETEs), was accompanied by a significant reduction in BP and a significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist [14,15-epoxyeicosa-5(Z)-enoic acid], supporting the notion that the improved cardiac ischaemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.
Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic. neckar@biomed.cas.cz
Jan
J
Neckář
Libor
L
Kopkan
Zuzana
Z
Husková
František
F
Kolář
František
F
Papoušek
Herbert J
HJ
Kramer
Sung Hee
SH
Hwang
Bruce D
BD
Hammock
John D
JD
Imig
Jiří
J
Malý
Ivan
I
Netuka
Bohuslav
B
Ošťádal
Luděk
L
Červenka
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001565:Benzoates / Q000494:pharmacology*; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015777:Eicosanoids / Q000378:metabolism / Q000652:urine; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D000959:Antihypertensive Agents; D001565:Benzoates; D002316:Cardiotonic Agents; D015777:Eicosanoids; D000804:Angiotensin II; D014508:Urea; D004851:Epoxide Hydrolases