Basic biology and pharmacology of the cardiac sarcolemmal sodium/hydrogen exchanger

Abstract

The Na+/H+ exchangers are a family of membrane proteins that transport sodium and hydrogen ions in opposite directions on a one-to-one basis, and play important roles in regulating cytoplasmic pH and cell volume and mediating sodium reabsorption in various tissues. In the myocardium, the physiological role of the exchanger is pH regulation. However, ischemic activation of the Na+/H+ exchanger in myocardium ultimately leads to intracellular calcium overload, a key mediator of ischemia and reperfusion injury. Studies in a wide variety of animal models have clearly shown that selective inhibition of the sarcolemmal Na+/H+ exchanger can delay progression of injury during ischemia, thereby reducing myocardial necrosis and improving recovery of ventricular function upon reperfusion. Furthermore, this inhibition does not adversely affect either the rate or degree of acidosis during ischemia. To be efficacious, Na+/H+ inhibition must be initiated before or during early ischemia; inhibition only during late ischemia and reperfusion has minimal to no beneficial effects. These preclinical data suggest that selective sodium hydrogen exchanger (NHE) inhibition may provide a new, efficacious treatment for acute myocardial ischemia in appropriate settings in humans.