Lipophilic HMG-CoA reductase inhibitors increase myocardial stunning in dogs.
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.
Satoh
K
K
Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan.
Ichihara
K
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood*; D004285:Dogs; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006439:Hemodynamics / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000503:physiopathology*; D010477:Perfusion; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D019821:Simvastatin / Q000494:pharmacology; D012995:Solubility; D013997:Time Factors
D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D000077340:Fluvastatin; D000255:Adenosine Triphosphate; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin