Na+/H+ exchanger: an emerging therapeutic target in cardiovascular disorders

Six isoforms of Na(+)/H(+) exchanger (NHE) have been identified to date. The NHE-1 isoform is expressed on the plasma membrane of cardiomyocytes and is involved in the regulation of intracellular pH and cell volume under normal physiological conditions. Myocardial ischemia-reperfusion is reported to strongly activate NHE-1. NHE-1 activation is postulated to contribute to myocardial injury by Ca(2+) overload. Several amiloride analogs non-selectively inhibit all isoforms of NHE and have been demonstrated to confer cardioprotection against ischemia-reperfusion injury in a number of experimental models with infarction, contractility, enzyme release and arrhythmias as endpoint. Recently, several selective inhibitors of the NHE-1 isoform have been synthesized and tested for their cardioprotective effect in animal models of ischemia-reperfusion injury. Cariporide and eniporide are currently being evaluated in phase II clinical trials for their antiischemic efficacy. NHE activity is reported to be altered in lymphocytes and vascular smooth muscle cells of spontaneously hypertensive rats and hypertensive patients. However, further research is required to clarify the role of NHE in the pathogenesis of hypertension. Several mitogenic stimuli are reported to activate NHE. Results of studies evaluating the effect of NHE inhibitors on postinfarction-induced cardiac remodeling in animals are promising. Further investigations are being carried out to highlight the involvement of NHE in cardiac hypertrophy. Based on the available data, it can be suggested that NHE has emerged as a useful target site in myocardial ischemia and may become a novel site for pharmacological modulation in hypertension and cardiac hypertrophy.