Simvastatin restores ischemic preconditioning in the presence of hyperglycemia through a nitric oxide-mediated mechanism

Background. A growing body of evidence indicates that statins decrease perioperative cardiovascular risk and that these drugs may be particularly efficacious in diabetes. Diabetes and hyperglycemia abolish the cardioprotective effects of ischemic preconditioning (IPC). The authors tested the hypothesis that simvastatin restores the beneficial effects of IPC during hyper-glycemia through a nitric oxide-mediated mechanism. Methods: Myocardial infarct size was measured in dogs (n = 76) subjected to coronary artery occlusion and reperfusion in the presence or absence of hyperglycemia (300 mg/dl) with or without IPC in separate groups. Additional dogs received simvastatin (20 mg orally daily for 3 days) in the presence or absence of EPC and hyperglycemia. Other dogs were pretreated with N-nitro-L-arginine methyl ester (30 mg intracoronary) with or without IPC, hyperglycemia, and simvastatin. Results: Ischemic preconditioning significantly (P < 0.05) reduced infarct size (n = 7, 7 +/- 2%) as compared with control (n = 7, 29 +/- 3%). Hyperglycemia (n = 7), simvastatin (n = 7), N-nitro-L-arginine methyl ester alone (n = 7), and simvastatin with hyperglycemia (n = 6) did not alter infarct size. Hyperglycemia (n = 7, 24 +/- 2%, but not N-nitro-L-arginine methyl ester (n = 5, 10 +/- 1%), blocked the protective effects of EPC. Simvastatin restored the protective effects of EPC in the presence of hyperglycemia (n = 7, 14 +/- 1%, and this beneficial action was blocked by N-nitro-L-arginine methyl ester (n = 7, 29 +/- 4%). Conclusions: The results indicate that simvastatin restored the cardioprotective effects of IPC during hyperglycemia by nitric oxide-mediated signaling. The results also suggest that enhanced cardioprotective signaling could be a mechanism for statin-induced decreases in perioperative cardiovascular risk.