TY - JOUR
T1 - Cytochrome P450 ω-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal K ATP channel
AU - Gross, Eric R.
AU - Nithipatikom, Kasem
AU - Hsu, Anna K.
AU - Peart, Jason N.
AU - Falck, John R.
AU - Campbell, William B.
AU - Gross, Garrett J.
N1 - Funding Information:
This work was supported by NIH grant HL74314-01 (G.J.G.) and American Heart Predoctoral and Postdoctoral Fellowships (Northland, E.R.G. and J.N.P.). Primary antibodies against CYP4A1 and CYP4A2 were gifts from Dr. J.H. Capdevila (Vanderbilt University Medical School) and CYP4F from Dr. D.R. Harder (Medical College of Wisconsin).
PY - 2004/12
Y1 - 2004/12
N2 - 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 K ATP channels (sK ATP and mK ATP) 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 sK ATP by HMR-1098 or mK ATP 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 sK ATP channel during reperfusion.
AB - 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 K ATP channels (sK ATP and mK ATP) 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 sK ATP by HMR-1098 or mK ATP 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 sK ATP channel during reperfusion.
KW - 20-HETE
KW - Cytochrome P450
KW - Ischemia
KW - K
KW - Reperfusion
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U2 - 10.1016/j.yjmcc.2004.10.008
DO - 10.1016/j.yjmcc.2004.10.008
M3 - Article
C2 - 15572055
AN - SCOPUS:9644279413
SN - 0022-2828
VL - 37
SP - 1245
EP - 1249
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -