Na+/H+ exchange inhibitors: a new class of cardioprotectors

摘要

The Na+/H+ exchanger (NHE) extrudes intracellular H+ in exchange for Na+ in an electroneutral process. Of the 6 mammalian exchanger isoforms identified to date, the NHE-1 is believed to be the molecular homologue of the sarcolemma Na+/H+ transporter. The exchanger is activated primarily by a reduction in intracellular pH, although such activation is subject to modulation by a variety of endogenous mediators (catecholamines, thrombin, endothelin) through receptor-mediated mechanisms. A large body of animal studies using both in vitro and in vivo models indicates that the inhibition of the sarcolemma NHE-1 attenuates myocardial injury in ischemia and reperfusion. Cardioprotective effects of NHE-1 inhibition involve a reduced susceptibility to severe ventricular arrhythmia, augmentation of contractile function recovery, and limitation of infarction size during reperfusion. Such protection is likely to arise partly from attenuation of "Ca2+ overload" in ischemic cardiomyocytes, which has been causally linked with all these pathologic phenomena. A marked benefit that has been observed with cariporide (HOE-642) and its structurally related congener HOE-694 in patients with acute myocardial infarction and in cardiac surgery demonstrates that selective NHE-1 inhibitors represent a novel and effective class of cardioprotectors.