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. Male Sprague-Dawley rats fed 2%
cholesterol-enriched chow for 8 weeks were subjected to
sevoflurane preconditioning (2.4% vol/vol, 1 h) 24 h before
myocardial ischemia was induced by occluding the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. 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-2, and Bad was assessed before
ischemia. 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, 1 mg/kg; i.v., 10 min before
ischemia), a selective inducible NOS (iNOS) inhibitor, and 5-hydroxy decanoate
sodium (5 mg/kg, i.v., 10 min before
ischemia), a mitochondrial
ATP-dependent K⁺ channel blocker. Such cardiac improvement induced by delayed
sevoflurane preconditioning did not occur in hypercholesterolemic rats and was not exacerbated by 1400W or 5-hydroxy decanoate
sodium. The expression of myocardial iNOS was markedly enhanced by delayed
sevoflurane preconditioning in normocholesterolemic, but not in hypercholesterolemic rats. The expression of endothelial NOS and Bad did not differ among all groups. The expression of myocardial phosphorylated endothelial NOS, Bcl-2, and 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. 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/mitochondrial
ATP-dependent K⁺ channel pathway.