The Myocardial Na[sup +] /H[sup +] Exchanger: A Potential Therapeutic Target for the Prevention of Myocardial Ischaemic and Reperfusion Injury and Attenuation of Postinfarction Heart Failure

Karmazyn, Morris; Sostaric, John V.; Gan, Xiaohong Tracey
February 2001
Drugs;Feb2001, Vol. 61 Issue 3, p375
Academic Journal
The myocardial Na[sup +] /H[sup +] exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. However, there is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The mechanism for this most probably reflects the fact that activation of the exchanger is closely coupled to Na[sup +] influx and therefore to elevation in intracellular Ca[sup 2+] concentrations through the Na[sup +] /Ca[sup 2+] exchange. The NHE is exquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects via phosphorylation-dependent processes. These generally represent various autocrine and paracrine as well as hormonal factors such as endothelin-1, angiotensin II and α[sub 1] -adrenoceptor agonists, which probably act through receptor-signal transduction processes.Thus far, 6 NHE isoforms have been identified and designated as NHE1 through NHE6. All except NHE6, which is located intracellularly, are restricted to the sarcolemmal membrane. In the mammalian myocardium the NHE1 subtype is the predominant isoform, although NHE6 has also been identified in the heart. The predominance of NHE1 in the myocardium is of some importance since, as discussed in this review, pharmacological development of NHE inhibitors for cardiac therapeutics has concentrated specifically on those agents which are selective for NHE1.These agents, as well as the earlier nonspecific amiloride derivatives have now been extensively demonstrated to possess excellent cardioprotective properties, which appear to be superior to other strategies, including the extensively studied phenomenon of ischaemic preconditioning. Moreover, the salutary effects of NHE inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of the NHE in mediating injury is not species spe...


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