Role of K+ATP channels in ischemic preconditioning and cardioprotection

Since the phenomenon of ischemic preconditioning was first described some 15 years ago, interest in strategies aimed at reducing infarct size has increased. During the past 10 years, investigations into the mechanism of ischemic preconditioning have clearly demonstrated the cardioprotective effect of K(ATP)(+) channel opening. Thus, K(ATP)(+) channel activation has been shown to be involved in this protection by a variety of stimuli, including a brief period of complete ischemia (classic ischemic preconditioning) or a partial coronary artery occlusion. In addition, ischemia in remote organs and nonischemic stimuli in the heart such as ventricular pacing, stretch, and heat stress also confer protection via K(ATP)(+) channel activation. Pharmacological agents that open K(ATP)(+) channels reduce infarct size, but K(ATP)(+) channel opening must occur prior to or early during the sustained infarct-producing coronary artery occlusion, while the degree and memory of cardioprotection are less than those produced by classic ischemic preconditioning. Although the exact mechanism by which K(ATP)(+) channel activation protects is still incompletely understood, recent studies indicate a role for the mitochondrial K(ATP)(+) channels. Before K(ATP)(+) channel opening can be employed in patients at increased risk of developing myocardial infarction (e.g., unstable angina), it is mandatory to determine whether tolerance (tachyphylaxia) occurs with repeated administration of K(ATP)(+) channel openers in a fashion similar to what occurs with ischemic preconditioning.