ISCHEMIC MYOCARDIAL-CELL PROTECTION CONFERRED BY THE OPENING OF ATP-SENSITIVE POTASSIUM CHANNELS

The responses of the cardiac myocyte to a potentially injurious ischem ic stress are multiple. The opening of the ATP-sensitive K+ channels m ay constitute one such response. These channels are present in the pla smalemma at very elevated density and have a large unitary conductance . Consequently, the opening of a small fraction (0.01-0.1%) of these c hannels during ischemia can help to drive the myocyte into an ''emerge ncy'' state, in which its syncytial functions become rapidly downregul ated and strategies appropriate to preserving cell viability are imple mented. Thus, ATP-sensitive K+ channels in cardiac myocytes would appe ar to be an efficient and apparently redundant natural means of defens e against metabolic stress. These channels can undergo physiologic mod ulation, as occurs during cardiac ischemic preconditioning in several species, including humans. The term cardioprotection refers to an endo genous cardioprotective strategy, whereby the myocardium slows its ene rgy demands, produces fewer toxic glycolytic products, and exhibits re duced injury following a potentially lethal ischemic stress. Openers o f cardiac ATP sensitive K+ channels, a class of drugs that includes, i n particular, aprikalim and nicorandil, also afford cardioprotection b y reducing the functional and biochemical damage produced by ischemia. Hence, these compounds can improve the recovery of cardiac contractil ity, reduce the extracellular leakage of intracellular enzymes, delay the loss of ATP, and preserve the cell ultrastructure in isolated hear t preparations subjected to transient ischemic conditions. Furthermore , when segmental contractility has been strongly depressed by a stunni ng insult, nicorandil and aprikalim can accelerate recovery at the rep erfusion. Finally, nicorandil and aprikalim decrease substantially the size of the necrotic region that results from a prolonged ischemic in sult followed by reperfusion. All of these desirable effects of K+-cha nnel openers can be abolished by blockers of ATP-sensitive K+ channels , such as glibenclamide. The fundamental mechanism of the myocyte viab ility protection conferred by K+ channel openers is not yet clear. It may exploit some of the same pathways that mediate cardiac ischemic pr econditioning. If this suggestion holds true, drugs opening cardiac AT P-sensitive K+ channels would mimic, exploit, or intensify those cardi oprotective means that are naturally available to the cardiac myocyte for overcoming metabolic stress.