THE SODIUM-HYDROGEN EXCHANGE SYSTEM IN THE HEART - ITS ROLE IN ISCHEMIC AND REPERFUSION INJURY AND THERAPEUTIC IMPLICATIONS

OBJECTIVES: To review evidence supporting a role for sodium-hydrogen e xchange (Na/H exchange) in mediating myocardial ischemic and reperfusi on injury, and to outline clinical implications in terms of the develo pment of novel cardioprotection strategies. DATA SOURCES: Various sour ces were used including MEDLINE and Reference Update. Only articles wr itten in the English language were used. DATA EXTRACTION: A wide range of publications dealing with cardiac injury and particularly studies involving intracellular pH regulation and Na/H exchange activity. The vast majority of papers cited were published since 1986, with a large percentage appearing within the past five years. DATA SYNTHESIS: Na/H exchange is a major mechanism for restoration of intracellular pH afte r ischemia, although its activation during both ischemia and reperfusi on has been shown to be involved in a paradoxical induction of cell in jury. This likely reflects the fact that activation of the exchanger i s closely coupled to sodium influx and, as a consequence, to elevation in intracellular calcium concentrations through sodium calcium exchan ge. in addition to intracellular acidosis, other factors can stimulate the exchanger, including various autocrine and paracrine factors such as endothelin-1 and activation of alpha(1) adrenergic receptors, both of which likely act through signal transduction processes including a ctivation of protein kinase C. Although at least 5 Na/H exchange isofo rms have been identified, it appears that subtype 1, termed NHE-1, is the predominant isoform in the mammalian myocardium. Effective pharmac ological inhibitors of Na/H exchange, including those that are NHE-1 s pecific, have been developed. These have been extensively demonstrated to protect the ischemic and reperfused myocardium, as shown by improv ed systolic and diastolic function, preservation of cellular ultrastru cture and reduced incidence of arrhythmias. Moreover, the salutary eff ects of these agents have been demonstrated by a variety of experiment al models and animal species, suggesting that the role of Na/H exchang e in mediating injury is not species-specific. CONCLUSION: Na/H exchan ge is an important target for pharmacological intervention in attenuat ion of ischemia- and reperfusion-induced cardiac injury. Coupled with the low potential for toxicity by the agents, Na/H exchange inhibition could emerge as an effective therapeutic strategy in cardiac disorder s, particularly involving conditions associated with ischemia and repe rfusion.