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Simvastatin Restores the Cardioprotective Effect of Ischemic Preconditioning in the Presence of Hyperglycemia through a NO-Mediated Mechanism
Weidong Gu, M.D.; John F. LaDisa, M.S.; Paul S. Pagel, M.D., Ph.D.; David C. Warltier, M.D., Ph.D.; Judy R. Kersten, M.D.
Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Introduction: Hyperglycemia inhibits and simvastatin enhances NO-mediated pathways. We previously demonstrated that hyperglycemia abolishes the cardioprotective effect of ischemic preconditioning (IPC). Therefore, we tested the hypothesis that simvastatin restores the ability of IPC to reduce myocardial infarct size in the presence of hyperglycemia in vivo through a NO-mediated mechanism.

Methods: After Animal Care Committee approval, barbiturate-anesthetized dogs (n=77) were instrumented for measurement of hemodynamics including aortic and left ventricular (LV) pressure and LV +dP/dtmax. Myocardial infarct size and coronary collateral blood flow were assessed with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. All dogs were subjected to a 60 min left anterior descending coronary artery occlusion followed by 3 hr of reperfusion. Dogs were randomly assigned to receive saline or 15% dextrose in water to increase blood glucose concentration to 300 mg/dl with or without IPC in 4 separate experimental groups. The effects of simvastatin were investigated in 2 additional groups of dogs treated with oral simvastatin (20 mg/kg for 3 days) in the presence or absence of IPC and hyperglycemia. The role of NO was evaluated in 3 final groups of dogs pretreated with L-NAME in the presence or absence of IPC and hyperglycemia. Statistical analysis of data was performed with ANOVA followed by the Student-Newman-Keuls test. Data are mean ± SEM.

Results: There were no differences in hemodynamics, area at risk for infarction or collateral blood flow among groups. Myocardial infarct size was 33±3% of the LV area at risk in control experiments. IPC significantly (P<0.05) reduced infarct size to 7±2%. Hyperglycemia, simvastain and L-NAME alone did not alter infarct size (27±2%, 27±3% and 31±3%, respectively). Hyperglycemia (24±2%), but not L-NAME (10±2), blocked the protective effects of IPC. Simvastatin restored the protective effect of IPC in the presence of hyperglycemia (14±1%), and this beneficial effect was blocked by L-NAME (29±4%).

Conclusions: Simvastatin restores the cardioprotective effect of IPC in the presence of hyperglycemia and this action is blocked by L-NAME. The results suggest that signal transduction during IPC is modulated by hyperglycemia and simvastatin through a NO-mediated mechanism.

Anesthesiology 2002; 96: A603