Attenuation of postcardioplegia injury with inhibitors of the sodium-hydrogen exchanger.

See related article on page 1442. T here is increasing evidence that the myocardial necrosis that occurs during coronary artery bypass grafting (CABG) surgery is due to, in part, inadequate myocardial protection and that one of the underlying mechanisms is related to activation of the sodium-hydrogen exchanger (NHE). The NHE is one of 2 intracellular alkalinizing exchangers in mammalian cells; the second mechanism is the NaHCO3 exchanger. To date, 7 different isoforms of the NHE have been identified and are termed NHE-1 through NHE-7. NHE-1 is the primary isoform in mammalian myocardium. It is a 110-kd glycosylated protein localized in the sarcolemmal membrane of the cardiomyocyte. Its activity is regulated, in part, by a proton sensor on the cytosolic surface of the exchanger that is sensitive to intracellular H concentration ([H ]i). In the resting state the NHE-1 is relatively quiescent, but during ischemia, increased intracellular accumulation of H stimulates the proton sensor, and activity of the exchanger is, in turn, increased by allosteric modifications of the molecule. The NHE-1 is also stimulated by other exogenous stimuli, such as cytokines, endothelin 1 (ET-1), thrombin, -adrenergic agents, and byproducts of ischemic metabolism, such as hydrogen peroxide and lysophosphatidylcholine. NHE-1 activity has been implicated as a mechanism underlying both myocardial and endothelial cell dysfunction caused by ischemia-reperfusion injury. During ischemia, the associated increase in [H ]i caused by anaerobic metabolism stimulates the NHE-1, which leads to a concomitant increase in intracellular Na concentration ([Na ]i). Extrusion of Na ions is limited, however, by the inhibition of the Na -K adenosine triphosphatase pump that occurs as a result of ischemiainduced depletion of adenosine triphosphate. The increased [Na ]i slows or reverses the direction of the Na /Ca exchanger, which normally extrudes Ca in exchange for Na when operating in the forward direction. This reversal results in a deleterious increase in intracellular Ca , which is known as intracellular calcium overload. This process is thought to be one of the key mechanisms underlying ischemia-reperfusion injury in the heart, manifested as contractile dysfunction, endothelial injury, necrosis, and apoptosis. It is important to note that it is not the NHE-1 activation per se that directly results in myocyte injury and cell death but rather its indirect effect associated with inhibition of Na -K adenosine triphosphatase and activity normally designed to prevent intracellular Na overload. As a consequence of the deleterious physiologic effects of Ca overload indirectly triggered by NHE-1 activity, a number of compounds have been developed to inhibit its activity, such as HOE 642 or cariporide. The long-term objective is to use these compounds to treat patients at risk of ischemia-reperfusion injury (ie, patients who undergo CABG surgery). Most experimental studies have demonstrated that NHE-1 inhibition is associated with a reduction in postischemic arrhythmias, necrosis, contractile dysfunction, and apoptosis. The preponderance of data suggest that these beneficial effects are exerted when the agent is administered before ischemia rather than afterward (ie, during reperfusion). There is evidence suggesting that prolonged ischemia might reduce the activity of the exchanger, and the exchanger could be stimulated at the time of reperfusion. However, results have been variable when NHE-1 inhibitors have been administered at reperfusion. Although cariporide was administered perioperatively in the GUARDIAN clinical From the Section of Cardiothoracic Surgery, The Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, Ga, and the Department of Surgery, University of Kentucky, Lexington, Ky.