MODULATION OF ISCHEMIA BY REGULATION OF THE ATP-SENSITIVE POTASSIUM CHANNEL

During acute myocardial ischemia, passage of potassium ions across the sarcolemma to the extracellular space is a well-established phenomenon. A recent hypothesis is that the ATP-dependent potassium channel plays a role in contributing to the potassium loss. As the potassium loss starts while the overall level of ATP is still relatively high, and as the channel is inhibited by rather low concentrations of ATP, the question arises as to how the channel is opened. Among the proposals are that, in addition to the total concentration of ATP, there is modulation of the regulation by its breakdown products, such as ADP and adenosine. Alternatively, or in addition, breakdown products of anaerobic glycolysis, such as lactate and protons, may also play a role. Extracellular acidosis may help to activate the channel, and internal lactate accumulation may have a similar effect. In certain circumstances there is evidence that ATP produced by glycolysis plays a significant role in the control of potassium channel activity. The concept of subsarcolemmal ATP is another explanation for the activation of the channel at relatively high ATP concentrations. Potassium channel closing drugs, such as glibenclamide, may prolong the action potential duration (shortened by ischemia) and thereby decrease the incidence of early ventricular arrhythmias. This same category of drugs may reduce early potassium loss from the ischemic tissue, thereby lessening the potentially protective effect of the external accumulation of potassium on the ischemic zone, the so-called local cardioplegic effect. Conversely, drugs of the potassium channel activating group are likely to have opposite effects on these arrhythmias and on myocardial protection. Channel activators may specifically benefit torsades de pointes. The net overall effects of such drugs are complex and include indirect benefits to the ischemic zone attained by coronary artery vasodilation as well as by local cardioplegia, and a decrease of reperfusion injury. According to the end point examined, it is possible to argue that any of these drugs (potassium channel opening or closing drugs) could be harmful or beneficial in the setting of acute regional ischemia.