Mechanisms of protection of the ischemic and reperfused myocardium by sodium-hydrogen exchange inhibition

Sodium-hydrogen exchange (Na-H exchange) is a major regulator of intracellu lar pH and is one of the major mechanisms for restoring pH after ischemia-i nduced intracellular acidosis. However, activation of Na-H exchange during ischemia and reperfusion is also involved in paradoxical induction of cell injury. This likely reflects the fact that activation of the exchanger is c losely coupled to sodium influx and, as a consequence, to elevation in intr acellular calcium concentrations through sodium-calcium exchange. In additi on to intracellular acidosis, other factors can also stimulate the exchange r, including various autocrine and paracrine factors, such as endothelin-1, angiotensin II, alpha(1)-adrenergic agonists, as well as toxic agents, suc h as hydrogen peroxide and lysophosphatidylcholine. Although at least six N a-H exchange isoforms have thus far been identified, it appears that the 1 subtype, termed NHE1, is the predominant isoform in the mammalian myocardiu m. Effective pharmacological inhibitors of Na-H exchange, including those t hat are NHE1 specific, have been extensively demonstrated to protect the is chemic and reperfused myocardium in terms of improved systolic and diastoli c function, preservation of cellular ultrastructure, attenuation of the inc idence of arrhythmias, and reduction of apoptosis. Moreover, the salutary e ffects of these agents have been demonstrated using a variety of experiment al models as well as animal species, suggesting that the role of Na-H excha nge in mediating injury is not species specific. Thus, Na-H exchange repres ents an important target for pharmacological intervention in attenuation of ischemia and reperfusion-induced cardiac injury. Coupled with the low pote ntial for toxicity of the agents, Na-H exchange inhibition could emerge as an effective therapeutic strategy in cardiac disorders, particularly involv ing conditions associated with ischemia and reperfusion.