Cytochrome P450 ω-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel

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Title Cytochrome P450 ω-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel
Author Gross, Eric R.; Nithipatikom, Kasem; Hsu, Anna K.; Peart, Jason Nigel John; Falck, John R.; Campbell, William B.; Gross, Garrett J.
Journal Name Journal of Molecular and Cellular Cardiology
Year Published 2004
Place of publication United Kingdom
Publisher Academic Press
Abstract Inhibition of 20-hydroxyeicosatrienoic acid (20-HETE), by pretreatment with pharmacological inhibitors of cytochrome P450 (CYP) ω-hydroxylase, has been shown to reduce infarct size in canines when administered prior to ischemia. However, it is unknown whether these agents reduce infarct size when administered just prior to reperfusion and if the sarcolemmal and/or mitochondrial KATP channels (sKATP and mKATP) contribute to cardioprotection. Therefore, we determined whether specific CYP inhibitors for epoxygenases and ω-hydroxylases are cardioprotective when given either prior to ischemia or prior to reperfusion and furthermore, if selective inhibition of the sKATP by HMR-1098 or mKATP by 5-hydroxydecanoic acid (5-HD) could abrogate this effect. Male Sprague–Dawley rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. Groups received either miconazole (MIC, non-selective CYP inhibitor, 3 mg/kg), 17-octadecynoic acid (17-ODYA, CYP ω-hydroxylase inhibitor, 0,3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, CYP ω-hydroxylase inhibitor, 0,4 or 4 mg/kg), N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH, CYP epoxygenase inhibitor, 3 mg/kg), or vehicle either 10 minutes prior to ischemia or 5 minutes prior to reperfusion. Rats also received either HMR-1098 (6 mg/kg) or 5-HD (10 mg/kg) 10 minutes prior to reperfusion, with subsets of rats also receiving either MIC or 17-ODYA 5 minutes prior to reperfusion. DDMS and 17-ODYA dose dependently reduced infarct size. Rats treated with MIC, 17-ODYA and DDMS, but not MS-PPOH, produced comparable reductions in infarct size when administered prior to ischemia or reperfusion compared to vehicle. HMR-1098, but not 5-HD, also blocked the infarct size reduction afforded by MIC and 17-ODYA. These data suggest a novel cardioprotective pathway involving CYP ω-hydroxylase inhibition and subsequent activation of the sKATP channel during reperfusion.
Peer Reviewed Yes
Published Yes
Alternative URI
Volume 37
Issue Number 6
Page from 1245
Page to 1249
ISSN 0022-2828
Date Accessioned 2006-07-26
Language en_AU
Research Centre Menzies Health Institute Qld; Heart Foundation Research Centre
Faculty Griffith Health Faculty
Subject PRE2009-Clinical Pharmacology and Therapeutics
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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