Na+/H+ exchange and pH(i) regulation in cardiac myocytes: physiology and pathophysiology

Intracellular pH (pH(i)) call exert profound effects on cardiac function an d the cardiac myocyte possesses regulated mechanisms for maintaining intrac ellular pH at physiological values. Among these processes, the sodium-hydro gen exchanger (NHE) represents a major mode of proton extrusion after acido sis, although other regulatory processes such as bicarbonate-dependent tran sporters are also of importance, At the present time, six exchanger genes a re known to exist in mammals. NHE1 has been recognized for some time as the ubiquitous <<housekeeping>> isoform. It is the sole isoform detectable in the cardiac myocyte and its function anti regulation has the greatest relev ance for cardiovascular physiology and pathology. The activity of NHE1 call be modulated by a number of growth factors, hormones and neurotransmitters . There is extensive evidence supporting the concept that the Na+/H+ exchan ge represents an effective target for pharmacologic intervention for the pr otection of the ischemic and reperfused myocardium. Earlier studies have re lied to a large degree on the use of amiloride or amiloride analogues to as sess the role of the exchanger in tissue injury. Their conclusions, which a re based on the assumption that the amiloride effect is mediated by its spe cificity for NHE, are reinforced by the more recent studies in which a diff erent class of highly potent NHE1 inhibitors with dissimilar structure (suc h as the HOE 642) was used. Studies published within the past few years hav e indeed supported the concept of NHE1 involvement in myocardial ischemic a nd reperfusion injury. Although the activity of the exchanger can be stimul ated by ischemia, its stimulation is particularly strong at the time of rep erfusion. The idiosyncrasies of nature, however, are often suggestive of mu ch more complex consequences of homeostatic processes than are first appare nt, and NHE activation is no exception. Accordingly, experimental evidence has Shown that stimulation of the exchanger, despite its necessity for pH(i ) restoration after acidosis, may contribute (likely together with another Na+-dependent process, the Na+-HCO8- symport) to myocardial injury. The con comitant influx of sodium ions creates an ionic imbalance that can also res ult in elevations in intracellular calcium concentrations through sodium-ca lcium exchange, thus producing potentially deleterious calcium overloading conditions. Therefore, the Na+/H+ exchange is a paradoxical phenomenon beca use it is a major mechanism for restoration of pH(i) after ischemia. As a c onsequence, however, cell injury occurs.