Abstract
The sodium–hydrogen exchange (NHE), which extrudes protons for concomitant sodium influx, represents the primary mechanism by which the cardiac cell regulates its pH, particularly under excessive proton production. Despite this critical role, NHE, which is activated during both ischemia as well as reperfusion, has been shown to be involved in a paradoxical induction of cell injury. The mechanism for this is closely coupled to excessive sodium influx, which cannot be corrected because of ischemia‐induced inhibition of the sodium–potassium ATPase, the major pathway for sodium removal. This results in elevation in intracellular calcium concentrations through sodium–calcium exchange. Although seven NHE isoforms have thus far been identified (five cell membrane, two intracellular), the one subtype, termed NHE‐1, is the predominant isoform in the mammalian myocardium. NHE‐1‐specific inhibitors that have recently been developed, some of which are in clinical trials, have extensively demonstrated protection against ischemic and reperfusion injury as evidenced by improved function and infarct size reduction. In addition, virtually all NHE‐1 inhibitors have been demonstrated to be effective antiarrhythmic agents, and in some studies more so than classic antiarrhythmic drugs. For example, a number of studies have shown that NHE‐1 inhibitors markedly attenuate ischemia‐induced arrhythmias and can totally abolish reperfusion‐induced ventricular fibrillation. NHE‐1 inhibitors can also produce spontaneous defibrillation in a model of electrically induced cardiac arrest. As NHE is an electroneutral system, its inhibition does not directly affect cardiac electrical activity, and therefore the beneficial effects against arrhythmias likely reflect a response secondary to cardiac tissue preservation. Irrespective of precise mechanisms, NHE‐1 inhibition appears to represent an effective antiarrhythmic approach in addition to its well‐established ability to protect the ischemic and reperfused myocardium. Drug Dev. Res. 55:22–28, 2002. © 2002 Wiley‐Liss, Inc.