Hypercholesterolemia Abrogates Sevoflurane Induced Delayed Preconditioning Against Myocardial Infarct In Rats By Alteration Of Nitric Oxide Synthase Signaling

Objective:The aim of the current study was to determine whether hypercholesterolemia affects the delayed sevoflurane preconditioning against myocardial ischemia-reperfusion (IR) injury and, if so, the underlying mechanism.Methods:Male Sprague-Dawley rats fed2%cholesterol-enriched chow for8weeks were subjected to sevoflurane preconditioning (2.4%v/v,1h)24h before myocardial ischemia was induced by occluding the left anterior descending coronary artery for30min followed by reperfusion for120min. The hemodynamic parameters left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal rise/fall rate of left ventricular pressure were continuously monitored and myocardial infarct size was determined at the end of reperfusion. The protein expression of myocardial nitric oxide synthase (NOS), Bcl-2and Bad were assessed before ischemia.Results:We found that the left ventricular hemodynamic parameters during the whole IR procedure and the myocardial infarct size did not significantly differ between the normocholesterolemic and hypercholesterolemic control groups. The hemodynamic parameters were all markedly improved during the reperfusion period and the myocardial infarct size was significantly reduced by delayed sevoflurane preconditioning in normocholesterolemic rats, but all of these improvements were reversed by N-(3-(aminomethyl)benzyl) acetamidine (1400W,1mg/kg, i.v.,10min before ischemia), a selective inducible NOS (iNOS) inhibitor, and5-hydroxy decanoate sodium (5-HD,5mg/kg, i.v.,10min before ischemia), a mitochondrial ATP-dependent K+channel (mKATP) blocker. Such cardiac improvement induced by delayed sevoflurane preconditioning did not occur in hypercholesterolemic rats and was not exacerbated by1400W or5-HD. The expression of myocardial iNOS was markedly enhanced by delayed sevoflurane preconditioning in normocholesterolemic, but not in hypercholesterolemic rats. The expression of endothelial NOS (eNOS) and Bad did not differ among all groups. The expression of myocardial phosphorylated eNOS, Bcl-2and phosphorylated Bad in normocholesterolemic rats was not affected by delayed sevoflurane preconditioning, but was decreased in the hypercholesterolemic control group, and this was not reversed by sevoflurane, compared with the normocholesterolemic control group.Conclusion:Taken together, these results indicate that sevoflurane preconditioning exerts delayed cardioprotection against IR injury in normocholesterolemic rats, which is blocked by hypercholesterolemia potentially via interference with the iNOS/mKATP pathway.