Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion.

The characterization of various ion transport systems has led to a better understanding of the effects, which seem to take part in the impairment of ischemic and reperfused cardiac tissue. This review discusses the role of the Na+/H+ exchange system in the pathophysiology of ischemia and reperfusion and the beneficial effects of its inhibition. At the onset of ischemia intracellular pH (pHi) decreases due to anaerobic metabolism and ATP hydrolysis, leading to an activation of Na+/H+ exchange. This in turn increases intracellular Na+ (Na+i) and activates Na+/K+ ATPase, with a consecutive increase of energy consumption. Since cellular Na+ and Ca++ transport are coupled by the Na+/Ca++ exchange system, which depends on the Na+ gradient, the high Na+i leads to increased intracellular Ca++ (Ca++i). After a certain period, Na+/H+ exchange is inactivated by a decrease of extracellular pH. In case of reperfusion the acid extracellular fluid is washed out, which reactivates Na+/H+ exchange, leading to an unfavourably fast restoration of pHi and a second time to Na+ and Ca++i overflow. High Ca++i is assumed to be one of the main reasons for ischemic and reperfusion injury, like arrhythmias, myocardial contracture, stunning and necrosis. It seems that the inhibition of Na+/H+ exchange can interrupt this process at an early phase and prevent or delay the consequences of ischemia and reperfusion as demonstrated by numerous investigators.