Regulation of Cardiac Sarcolemmal Na+/H+ Exchanger Activity: Potential Pathophysiological Significance of Endogenous Mediators and Oxidant Stress

The cardiac sarcolemmal Na⁺/H⁺ exchanger (NHE) extrudes one H⁺ in exchange for one Na⁺ entering the myocyte, utilizing for its driving force the inwardly directed Na⁺ gradient maintained by the Na⁺, K⁺-ATPase. The exchanger is quiescent at physiological values of intracellular pH but becomes activated in response to intracellular acidosis. Recent evidence suggests that a variety of extracellular signals (e.g., adrenergic agonists, thrombin, endothelin, and oxidant stress) also modulate sarcolemmal NHE activity by altering its sensitivity to intracellular H⁺. Because sarcolemmal NHE activity is believed to be an important determinant of the extent of myocardial injury during ischemia and reperfusion, regulation of exchanger activity by factors that are associated with ischemia is likely to be pathophysiological importance.