Role of cardiac ATP-sensitive K+ channels induced by HMG CoA reductase inhibitor in ischemic rabbit hearts.

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Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors can protect the myocardium against ischemic injury, the mechanisms of their effect have not yet been characterized at the cellular level. Therefore, we investigated the role of cardiac ATP-sensitive K+ (K(ATP)) channels induced by the HMG-CoA reductase inhibitor known as pravastatin on the myocardial metabolism during ischemia by phosphorus 31-nuclear magnetic resonance (31P-NMR) in isolated rabbit hearts. Forty-five min of continuous normothermic global ischemia was carried out. Pravastatin with or without the K(ATP) channel blocker glibenclamide or the nitric oxide synthase inhibitor L-NAME was administered beginning 60 min prior to the global ischemia. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each: the control group, the P group consisting of pravastatin treatment, the P+G group consisting of pravastatin treatment with glibenclamide, and the P+L group consisting of pravastatin treatment with L-NAME. During ischemia, the decreases in adenosine triphosphate (ATP) and intracellular pH (pHi) were significantly inhibited in the P group in comparison with Control group (at end of ischemia, respectively; both p<0.01), as was the increase in inorganic phosphate (Pi) (at end of ischemia, p<0.01). However, the decreases in ATP and pHi and the increase in Pi were not inhibited in the P+G group during ischemia. The P+L group also showed no inhibition of the aforementioned parameters during the same period. These results suggest that pravastatin has a significant beneficial effect for improving the myocardial energy metabolism, which is provided by K(ATP) channels and nitric oxide (NO), during myocardial ischemia. The cardioprotection of HMG-CoA reductase inhibitor may be caused by the K(ATP) channels that are mediated by the NO.