Interaction of Exercise and Simvastatin on Myocardial Ischemia-Reperfusion (I-R) Injury

Abstract

Simvastatin is one of the statins, which are a class of drugs originally developed to fight cardiovascular disease by lowering cholesterol. However, it is now clear that they have effects independent of cholesterol. For example, statin therapy, like exercise, induces adaptations within the heart that protect it against I-R injury. Patients are frequently advised to undergo a combination treatment of statins and chronic exercise, although little is known about how this combination treatment affects cardioprotective adaptations. PURPOSE: To investigate the effects of a combination treatment of statins and exercise upon myocardial tolerance to ischemia and subsequent reperfusion. METHODS: Female Sprague-Dawley rats (6 months of age) were separated into 4 groups for a period of 4 weeks: Sedentary (S, n=17), sedentary plus 10 mg simvastatin (Zocor®)/kg body wt/ day (SD, n=17), exercise (R, n=17), and exercise plus simvastatin (RD, n=16). R and RD were exercised identically on a treadmill for 5 days/week at an intensity of about 70% VO2max and for a duration that was gradually increased to 60 min/day. Twenty-four hrs following the last exercise bout, isolated perfused working hearts from 35 of the animals (8–9/group) were subjected to 30 min of global ischemia followed by 30 min of normoxic reperfusion. Coronary effluents were used to determine lactate dehydrogenase (LDH) leakage and protaglandin release. Hearts of the other animals were briefly rinsed and used to measure enzyme activities and heat shock protein 70 (HSP70) content. RESULTS: Cardiac function was similar in all groups prior to ischemia. Post I-R recovery of cardiac function in S was 17.6±6.6% of pre-ischemic cardiac output times systolic pressure. Recovery was significantly higher in SD (37.7±7.7%) and R (40.1 ±7.7%) and tended to be highest in RD (49.7±7.1%). Compared to S, LDH leakage during reperfusion was dramatically decreased in SD, R and RD by approximately similar amounts. Simvastatin treatment doubled the production of protective pro stag landins, whereas exercise did not significantly alter their production. Exercise-induced increase in HSP70 was attenuated in RD compared to R (P<0.05). Both simvastatin (SD) and exercise (R) alone lowered mitochondrial superoxide dismutase activity compared to S (P<0.05), but combining the two treatments (RD) prevented the decline. Other antioxidant enzymes measured were similar in all groups. CONCLUSION: Exercise- and statin-induced cardioprotection against I-R injury appears to occur by different mechanisms and combining the two treatments may provide greater protection than either alone.