Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs

Pretreatment of dogs with simvastatin, a lipophilic 3-hydroxy-3-methylgluta ryl coenzyme A (HMG-CoA) reductase inhibitor, increases myocardial contract ile dysfunction during reperfusion after ischemia (stunning), with reductio n of tissue adenosine triphosphate (ATP). This was thought to be a conseque nce of prevention of ubiquinone biosynthesis by the lipophilic inhibitor in the myocardial cell. We examined whether other lipophilic HMG-CoA reductas e inhibitors also influence myocardial stunning in dogs. Vehicle, atorvasta tin (2 mg/kg/day), fluvastatin (4 mg/kg/day), or cerivastatin (40 mu g/kg/d ay) was orally administered for 3 weeks. Hydrophilic pravastatin (4 mg/kg/d ay) also was given. After 3 weeks, pentobarbital-anesthetized dogs were sub jected to 15-min left anterior descending coronary artery occlusion followe d by 2-h reperfusion. Myocardial segment function was determined by sonomic rometry. Tissue levels of ATP were determined in 2-h reperfused hearts. All inhibitors significantly decreased serum cholesterol level. The three lipo philic inhibitors resulted in a worsening of segment function in the reperf used myocardium, as compared with the vehicle group. The levels of ATP in t he atorvastatin, fluvastatin, and cerivastatin groups were significantly lo wer than that in the vehicle group. These results confirm that lipophilic H MG-CoA reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion.