Inhibition of 20-hydroxyeicosatrienoic
acid (20-HETE), by pretreatment with pharmacological inhibitors of
cytochrome P450 (
CYP) omega-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 omega-
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 omega-hydroxylase inhibitor, 0,3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (
DDMS,
CYP omega-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 omega-hydroxylase inhibition and subsequent activation of the sK(
ATP) channel during reperfusion.