Pravastatin reduces myocardial infarct size via increasing protein kinase C-dependent nitric oxide, decreasing oxyradicals and opening the mitochondrial adenosine triphosphate-sensitive potassium channels in rabbits

Abstract

Background: Statins reportedly protect against myocardial infarction, but the precise mechanism is unclear. Methods and Results: Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Pravastatin (1 or 5 mg/kg) or saline was intravenously administered 10 min before ischemia. Pravastatin (5 mg/kg) was also administered 10 min before reperfusion. N •-•nitro-L-arginine methylester (L-NAME, 10 mg/kg), chelerythrine (5 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg) was intravenously administered 10 min before pravastatin injection. The infarct size was determined. The myocardial interstitial levels of 2,5-dihydroxybenzoic acid (DHBA) and nitrogen oxide (NOx), and the intensity of myocardial dihydroethidium staining were measured. Pre-ischemic treatment with pravastatin reduced the infarct size (34±5% and 24±4%, 1 and 5 mg/kg, respectively), but not pre-reperfusion treatment (42.1±3.7%), compared with the control (45±3%). This effect was blocked by L-NAME (42.6±4%), chelerythrine (50.9±3%) and 5-HD (52.7±2%). Pre-ischemic treatment with pravastatin increased myocardial NOx levels, and attenuated both the 2,5-DHBA level and the intensity of dihydroethidium staining during reperfusion. Chelerythrine abolished the increase in NOx levels by pravastatin. Conclusion: Pre-ischemic treatment with pravastatin reduces the myocardial infarct size via protein kinase C-dependent nitric oxide production, decreasing hydroxyl radicals and superoxide, and opening the mitochondrial adenosine triphosphate-sensitive potassium channels.