Simvastatin-induced myocardial protection against ischemia-reperfusion injury is mediated by activation of ATP-sensitive K+ channels.
OBJECTIVE
Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors attenuate ischemia-reperfusion injury. We investigated whether pretreatment with simvastatin reduces myocardial infarct size and whether glyburide, a non-selective inhibitor of the ATP-sensitive K channels, abrogates this infarct size-limiting effect.


METHODS
Sprague-Dawley rats were treated with either simvastatin (20 mg/kg per day) or saline alone for 3 days. Additional groups of rats were treated as above and on the fourth day they received intravenous glyburide (0.3 mg/kg). All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size with triphenyltetrazolium chloride.


RESULTS
Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the simvastatin group (n = 8, 20.8 +/- 3.4%) than in the placebo group (n = 6, 40.1 +/- 2.7%) (P = 0.001). Glyburide abolished the protective effect of simvastatin with infarct size being 34.2 +/- 6.9% and 29.7 +/- 3.9% of the area at risk in the simvastatin group (n = 7) and placebo (n = 7) group, respectively (P = 0.58).


CONCLUSIONS
Simvastatin significantly reduced myocardial infarct size. The protective effect was completely abrogated by glyburide, strongly suggesting that this protective effect is mediated via activation of the ATP-sensitive K channels.
Tavackoli
Shahin
S
Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0553, USA.
Ashitkov
Taras
T
Hu
Zhao-Yong
ZY
Motamedi
Massoud
M
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003097:Collateral Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005905:Glyburide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008955:Models, Cardiovascular; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D015221:Potassium Channels / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013223:Statistics as Topic
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015221:Potassium Channels; D019821:Simvastatin; D005905:Glyburide