Lipophilic statin drugs worsen myocardial ischemia in dogs. - GreenMedInfo Summary
Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs.
J Cardiovasc Pharmacol. 2000 Feb ;35(2):256-62. PMID: 10672858
Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan.
Pretreatment of dogs with simvastatin, a lipophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, increases myocardial contractile dysfunction during reperfusion after ischemia (stunning), with reduction of tissue adenosine triphosphate (ATP). This was thought to be a consequence of prevention of ubiquinone biosynthesis by the lipophilic inhibitor in the myocardial cell. We examined whether other lipophilic HMG-CoA reductase inhibitors also influence myocardial stunning in dogs. Vehicle, atorvastatin (2 mg/ kg/day), fluvastatin (4 mg/kg/day), or cerivastatin (40 microg/kg/ day) was orally administered for 3 weeks. Hydrophilic pravastatin (4 mg/kg/day) also was given. After 3 weeks, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending coronary artery occlusion followed by 2-h reperfusion. Myocardial segment function was determined by sonomicrometry. Tissue levels of ATP were determined in 2-h reperfused hearts. All inhibitors significantly decreased serum cholesterol level. The three lipophilic inhibitors resulted in a worsening of segment function in the reperfused myocardium, as compared with the vehicle group. The levels of ATP in the atorvastatin, fluvastatin, and cerivastatin groups were significantly lower than that in the vehicle group. These results confirm that lipophilic HMG-CoA reductase inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and reperfusion.