Over the past few years, it has been shown that the cardiac myocyte plasma membrane
sodium ion/hydrogen ion exchanger (NHE) plays an important role in the maintenance of intracellular pH,
sodium, and
calcium ion homeostasis. From the results of various experimental studies, it is clear that this ion exchanger is an important mediator of ischemic-
reperfusion injury of the heart. During
myocardial ischemia, intracellular
acidosis develops quickly, activating the exchanger to extrude H+ into the extracellular environment and bring Na+ into the cell. With further progression of
ischemia, the cell is unable to handle the overload of Na+, causing it to use its Na+/Ca2 exchanger to unload intracellular Na+ into the extracellular space. At the same time, however,
calcium is being transported into the cell. This can lead to detrimental cardiac injury, such as
contracture and
necrosis. During myocardial reperfusion, these events are magnified because the return of blood flow lowers the extracellular H+ concentration, stimulating the NHE to extrude more intracellular H+ ion. This leads to intracellular Na+ excess and eventually, intracellular Ca2+ overload and cardiac injury. In an effort to alter these pathophysiologic events, a number of investigators have studied the ability of various NHE inhibitors, such as
amiloride, analogues of
amiloride, and other drugs (
HOE 694,
HOE 642), to prevent cardiac ischemic-
reperfusion damage. Preliminary results from studies in animal models have revealed that most of these agents are able to attenuate the development of myocardial
contracture,
infarction, and arrhythmias during both
ischemia and reperfusion. Their efficacy and cardioprotective effects in human beings have yet to be determined. These agents appear to be promising not only in the prevention and treatment of
ischemic heart disease, but also in avoiding cardiac damage in situations where low-flow states are followed by immediate recovery of flow, as in
coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty,
thrombolytic therapy, and coronary arterial vasospasm. This article reviews the physiology of the NHE and analyzes the potential role of NHE inhibitors in the prevention of ischemic-
reperfusion injury and other
cardiac disease states.