We investigated the effect of a newly synthesized compound,
SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-
indole-2-carboxamide
methanesulfonic acid] on Na+/H+ or Na+/Ca2+ exchange activity in rat cardiomyocytes, and on radioligand binding with several channels or receptors in membrane preparations, and
ischemia/reperfusion injury in isolated perfused rat hearts. In myocytes,
SM-20550 concentration-dependently inhibited the recovery from
acidosis induced by an NH4Cl prepulse in HCO3(-)-free
solution. Its IC50 was 10(-8) M, which was 10 times lower than that of ethylisopropyl
amiloride (
EIPA).
SM-20550 (10(-6) M) did not affect the Na+-dependent Ca2+ influx (Na+/Ca2+ exchange activity) in cardiomyocytes. In the radioligand binding assay,
SM-20550 did not have affinity for K+ channel, beta-
adrenoceptor,
adenosine,
angiotensin, or
endothelin receptors, and had low affinity for Na+ and Ca2+ channels and alpha-
adrenoceptors, only at the concentrations of 10(-6)-10(-5) M. In perfused hearts exposed to 40 min of global
ischemia and 20 min of reperfusion,
SM-20550 (10(-8)-10(-7) M) significantly reduced the elevation of left ventricular end-diastolic pressure during reperfusion, improved the postischemic recovery of developed pressure, and prevented coronary perfusion pressure increase after reperfusion. Furthermore,
SM-20550 reduced
creatine phosphokinase release during reperfusion and prevented the abnormal gain of tissue Na+ and Ca2+ at the end of reperfusion. These results suggest that
SM-20550 is a potent, highly specific Na+/H+ exchange inhibitor, which exerts a protective effect against
myocardial ischemia/
reperfusion injury. In addition, our data strongly support the hypothesis that Na+/H+ exchange plays an important role in the development of postischemic cardiac dysfunction, most likely by inducing Na+ and Ca2+ overload.