The sodium-hydrogen exchange system in the heart: its role in ischemic and reperfusion injury and therapeutic implications.
OBJECTIVE
To review evidence supporting a role for sodium-hydrogen exchange (Na/H exchange) in mediating myocardial ischemic and reperfusion injury, and to outline clinical implications in terms of the development of novel cardioprotection strategies.


METHODS
Various sources were used including MEDLINE and Reference Update. Only articles written in the English language were used.


METHODS
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.


RESULTS
Na/H exchange is a major mechanism for restoration of intracellular pH after ischemia, although its activation during both ischemia and reperfusion has been shown to be involved in a paradoxical induction of cell injury. This likely reflects the fact that activation of the exchanger is closely coupled to sodium influx and, as a consequence, to elevation in intracellular calcium concentrations through sodium-calcium exchange. 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 activation of protein kinase C. Although at least 5 Na/H exchange isoforms have been identified, it appears that subtype 1, termed NHE-1, is the predominant isoform in the mammalian myocardium. Effective pharmacological inhibitors of Na/H exchange, including those that are NHE-1 specific, have been developed. These have been extensively demonstrated to protect the ischemic and reperfused myocardium, as shown by improved systolic and diastolic function, preservation of cellular ultrastructure and reduced incidence of arrhythmias. Moreover, the salutary effects of these agents have been demonstrated by a variety of experimental models and animal species, suggesting that the role of Na/H exchange in mediating injury is not species-specific.


CONCLUSIONS
Na/H exchange is an important target for pharmacological intervention in attenuation 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 disorders, particularly involving conditions associated with ischemia and reperfusion.
Karmazyn
M
M
Department of Pharmacology and Toxicology, University of Western Ontario, London. mkarm@julian.uwo.ca
D000818:Animals; D002118:Calcium / Q000378:metabolism; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology*
D017923:Sodium-Hydrogen Exchangers; D002118:Calcium