Ischemic myocardial cell protection conferred by the opening of ATP-sensitive potassium channels

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Abstract
The responses of the cardiac myocyte to a potentially injurious ischemic stress are multiple. The opening of the ATP-sensitive K+ channels may constitute one such response. These channels are present in the plasmalemma at very elevated density and have a large unitary conductance. Consequently, the opening of a small fraction (0.01–0.1%) of these channels during ischemia can help to drive the myocyte into an “emergency” state, in which its syncytial functions become rapidly downregulated and strategies appropriate to preserving cell viability are implemented. Thus, ATP-sensitive K+ channels in cardiac myocytes would appear to be an efficient and apparently redundant natural means of defense against metabolic stress. These channels can undergo physiologic modulation, as occurs during cardiac ischemic preconditioning in several species, including humans. The termcardioprotection refers to an endogenous cardioprotective strategy, whereby the myocardium slows its energy demands, produces fewer toxic glycolytic products, and exhibits reduced injury following a potentially lethal ischemic stress. Openers of cardiac ATP-sensitive K+ channels, a class of drugs that includes, in particular, aprikalim and nicorandil, also afford cardioprotection by reducing the functional and biochemical damage produced by ischemia. Hence, these compounds can improve the recovery of cardiac contractility, reduce the extracellular leakage of intracellular enzymes, delay the loss of ATP, and preserve the cell ultrastructure in isolated heart preparations subjected to transient ischemic conditions. Furthermore, when segmental contractility has been strongly depressed by a stunning insult, nicorandil and aprikalim can accelerate recovery at the reperfusion. Finally, nicorandil and aprikalim decrease substantially the size of the necrotic region that results from a prolonged ischemic insult followed by reperfusion. All of these desirable effects of K+-channel openers can be abolished by blockers of ATP-sensitive K+ channels, such as glibenclamide. The fundamental mechanism of the myocyte viability protection conferred by K+-channel openers is not yet clear. It may exploit some of the same pathways that mediate cardiac ischemic preconditioning. If this suggestion holds true, drugs opening cardiac ATP-sensitive K+ channels would mimic, exploit, or intensify those cardioprotective means that are naturally available to the cardiac myocyte for overcoming metabolic stress.