Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-I-ylureido)cyclohexyloxy] benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension

Jan Neckár, 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

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39 Scopus citations

Abstract

The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-I-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.

Original languageEnglish (US)
Pages (from-to)513-525
Number of pages13
JournalClinical Science
Volume122
Issue number11
DOIs
StatePublished - Jun 2012

Keywords

  • Angiotensin II
  • Epoxyeicosatrienoic acid
  • Hypertension
  • Kidney
  • Myocardial ischaemia/reperfusion injury
  • Soluble epoxide hydrolase inhibitor

ASJC Scopus subject areas

  • Medicine(all)

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    Neckár, J., Kopkan, L., Husková, Z., Kolář, F., Papoušek, F., Kramer, H. J., Hwang, S. H., Hammock, B. D., Imig, J. D., Malý, J., Netuka, I., Ošťádal, B., & Červenka, L. (2012). Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-I-ylureido)cyclohexyloxy] benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension. Clinical Science, 122(11), 513-525. https://doi.org/10.1042/CS20110622