The cardiac sarcolemmal Na+/H+ exchanger extrudes intracellular H+ in exchange for Na+, in an electroneutral process. Of the 6 mammalian exchanger
isoforms identified to date, the Na+/H+ exchanger (NHE)-1 is believed to be the molecular homolog of the sarcolemmal Na+/H+ exchanger. The exchanger is activated primarily by a reduction in intracellular pH (intracellular
acidosis), although such activation is subject to modulation by a variety of endogenous mediators (e.g.,
catecholamines,
thrombin,
endothelin) through receptor-mediated mechanisms. A large body of preclinical evidence now suggests that inhibition of the sarcolemmal Na+/H+ exchanger attenuates many of the unfavorable consequences of acute
myocardial ischemia and reperfusion. Much of this evidence has been obtained with recently developed potent, selective inhibitors of the exchanger, such as
HOE-642 (
cariporide) and its structurally related congener
HOE-694, in studies using both in vitro and in vivo models of
ischemia and reperfusion in a variety of species. The data from these studies indicate that Na+/H+ exchange inhibition leads to a decreased susceptibility to severe ventricular
arrhythmia, attenuates contractile dysfunction, and limits tissue
necrosis (i.e., decreases
infarct size) during
myocardial ischemia and reperfusion. Such protection is likely to arise, at least in part, from attenuation of "Ca2+ overload," which has been linked causally with all of these pothologic phenomena. The consistent and marked cardioprotective benefit that has been observed with
cariporide and related compounds in preclinical studies suggests that Na+/H+ exchange inhibition may represent a novel and effective approach to the treatment of acute
myocardial ischemia in humans.