ROLE OF Na-H EXCHANGE (NHE-1) IN MYOCARDIAL ISCHAEMIA AND HYPERTROPHY

Morris Karmazyn, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.

The myocardial sodium-hydrogen exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. There is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The involvement of the myocardial NHE (NHE-1) in acute injury reflects the inability to extrude sodium by the ischaemic cardiac cell due to Na-K ATPase inhibition which occurs in concert with NHE-1 activation, the latter occurring as a consequence of increased proton generation during ischaemia. The extensive documentation demonstrating cardioprotective effects of NHE inhibitors has strongly supported the concept of the antiporter's involvement in cardiac injury, especially under conditions of ischaemia and reperfusion. A particularly striking feature of NHE-1 inhibitors is their ability to protect against various forms of dysfunctions including reduced mortality, limitation of infarct size, improvement of functional recovery after reperfusion, reduction of arrhythmias, attenuation of calcium and sodium dyshomeostasis, reduction of apoptosis and preservation of metabolic status. The excellent results obtained with NHE-1 inhibitors has led to clinical trials with these agents in patients with coronary artery disease. It is now emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. It appears, in fact, that NHE-1 inhibitors can reverse hypertrophy and heart failure when administered after infarction. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertrophic factors such as angiotensin II, endothelin-1 and α₁ adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure as well as protecting the ischaemic myocardium.