Coronary artery disease and its sequelae-
ischemia, myocardial infarction, and
heart failure-are leading causes of morbidity and mortality in man. Considerable effort has been devoted toward improving functional recovery and reducing the extent of
infarction after ischemic episodes. As a step in this direction, it was found that the heart was significantly protected against
ischemia-reperfusion injury if it was first preconditioned by brief
ischemia or by administering a
potassium channel opener. Both of these preconditioning strategies were found to require opening of a K(
ATP) channel, and in 1997 we showed that this pivotal role was mediated by the mitochondrial
ATP-sensitive K(+) channel (
mitoK(ATP)). This paper will review the evidence showing that opening
mitoK(ATP) is cardioprotective against
ischemia-reperfusion injury and, moreover, that
mitoK(ATP) plays this role during all three phases of the natural history of
ischemia-reperfusion injury preconditioning,
ischemia, and reperfusion. We discuss two distinct mechanisms by which
mitoK(ATP) opening protects the heart-increased mitochondrial production of
reactive oxygen species (ROS) during the preconditioning phase and regulation of intermembrane space (IMS) volume during the ischemic and reperfusion phases. It is likely that cardioprotection by ischemic preconditioning (IPC) and K(
ATP) channel openers (KCOs) arises from utilization of normal physiological processes. Accordingly, we summarize the results of new studies that focus on the role of
mitoK(ATP) in normal cardiomyocyte physiology. Here, we observe the same two mechanisms at work. In low-energy states,
mitoK(ATP) opening triggers increased mitochondrial ROS production, thereby amplifying a cell signaling pathway leading to gene transcription and cell growth. In high-energy states,
mitoK(ATP) opening prevents the matrix contraction that would otherwise occur during high rates of electron transport.
MitoK(ATP)-mediated volume regulation, in turn, prevents disruption of the structure-function of the IMS and facilitates efficient energy transfers between mitochondria and myofibrillar
ATPases.