The myocardial Na+/H+ exchanger - A potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation ofpostinfarction heart failure

The myocardial Na+/H+ exchange (NHE) represents a major mechanism for pH re gulation during normal physiological processes but especially during ischae mia and early reperfusion. However, there is now very compelling evidence t hat 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+ influx and therefore to elevation in in tracellular Ca2+ concentrations through the Na+/Ca2+ exchange. The NHE is e xquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects vi a phosphorylation-dependent processes. The se generally represent various autocrine and paracrine as well as hormo nal factors such as endothelin-1, angiotensin II and alpha (1)-adrenoceptor agonists, which probably act through receptor-signal transduction processe s. Thus far, 6 NHE isoforms have been identified and designated as NHE1 throug h NHE6. All except NHE6, which is located intracellularly, are restricted t o the sarcolemmal membrane. In the mammalian myocardium the NHE1 subtype is the predominant isoform, although NHE6 has also been identified in the hea rt. 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 whi ch are selective for NHE1. These agents, as well as the earlier nonspecific amiloride derivatives have now been extensively demonstrated to possess excellent cardioprotective pr operties, which appear to be superior to other strategies, including the ex tensively studied phenomenon of ischaemic preconditioning. Moreover, the sa lutary effects of NHE inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of t he NHE in mediating injury is not species specific. The success of NHE inhibitors in experimental studies has led to clinical t rials for the evaluation of these agents in high risk patients with coronar y artery disease as well as in patients with acute myocardial infarction (M I). Recent evidence also suggests that NHE inhibition may be conducive to a ttenuating the remodelling process after MI, independently of infarct size reduction, and attenuation of subsequent postinfarction heart failure. As s uch, inhibitors of NHE offer substantial promise for clinical development f or attenuation of both acute responses to myocardial as well as chronic pos tinfarction responses resulting in the evolution to heart failure.