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.
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February 10 2012
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
Jan Neckář;
*Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
†Center for Cardiovascular Research, Prague, Czech Republic
Correspondence: Dr Jan Neckář (email [email protected]).
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Libor Kopkan;
Libor Kopkan
†Center for Cardiovascular Research, Prague, Czech Republic
‡Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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Zuzana Husková;
Zuzana Husková
†Center for Cardiovascular Research, Prague, Czech Republic
‡Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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František Kolář;
František Kolář
*Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
†Center for Cardiovascular Research, Prague, Czech Republic
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František Papoušek;
František Papoušek
*Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
†Center for Cardiovascular Research, Prague, Czech Republic
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Herbert J. Kramer;
Herbert J. Kramer
§Section of Nephrology, Medical Polyclinic, Department of Medicine, University of Bonn, Bonn, Germany
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Sung Hee Hwang;
Sung Hee Hwang
‖Department of Entomology and UCD Cancer Center, University of California, Davis, CA, U.S.A.
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Bruce D. Hammock;
Bruce D. Hammock
‖Department of Entomology and UCD Cancer Center, University of California, Davis, CA, U.S.A.
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John D. Imig;
John D. Imig
¶Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
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Jiří Malý;
Jiří Malý
†Center for Cardiovascular Research, Prague, Czech Republic
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Ivan Netuka;
Ivan Netuka
*Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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Bohuslav Ošťádal;
Bohuslav Ošťádal
*Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
†Center for Cardiovascular Research, Prague, Czech Republic
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Luděk Červenka
Luděk Červenka
†Center for Cardiovascular Research, Prague, Czech Republic
‡Department for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
**Department of Physiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
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Publisher: Portland Press Ltd
Received:
December 01 2011
Accepted:
December 16 2011
Accepted Manuscript online:
December 16 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 122 (11): 513–527.
Article history
Received:
December 01 2011
Accepted:
December 16 2011
Accepted Manuscript online:
December 16 2011
Citation
Jan Neckář, Libor Kopkan, Zuzana Husková, František Kolář, František Papoušek, Herbert J. Kramer, Sung Hee Hwang, Bruce D. Hammock, John D. Imig, Jiří Malý, Ivan Netuka, Bohuslav Ošťádal, Luděk Červenka; 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. Clin Sci (Lond) 1 June 2012; 122 (11): 513–527. doi: https://doi.org/10.1042/CS20110622
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