Effect of SMP-300, a New Na+/H+ Exchange Inhibitor, on Myocardial Ischemia and Experimental Angina Models in Rats

We evaluated the effects of SMP-300 (N-(aminoiminomethyl)-11-chloro-5,6,7,8-tetrahydro-8-oxo-4H-pyrrolo[3,2,1-kl][1]benzazocine-2-carboxamide monomethanesulfonate monohydrate), a newly synthesized compound, on Na+/H+ exchange activity in rat cardiomyocytes and on other ion transporters, channels and receptors. We also investigated the protective effects of SMP-300 in isolated ischemic rat hearts and rat isoproterenol- or vasopressin-induced experimental angina models. SMP-300 concentration-dependently inhibited recovery from acidosis in rat myocytes, and its IC50 for Na+/H+ exchange was 6 nM. In comparison, its IC50s for Na+/Ca2+ exchange and for the Na+ channel were >1000 nM, and those for other channels or receptors tested were >10,000 nM. In rat isolated perfused hearts, SMP-300 (10(-8)-10(-7) M), administered only at preischemia and not during reperfusion, significantly improved the postischemic recovery of cardiac function. SMP-300 (0.03-0.3 mg/kg, i.v.) or 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) prevented the isoproterenol-induced ST-segment depression in the ECG of anesthetized rats, in a dose-dependent manner. SMP-300 (0.1 mg/kg, i.v.) and 5-(N-ethyl-N-isopropyl)-amiloride (1 mg/kg, i.v.) also inhibited the vasopressin-induced ST-segment depression in the ECG of anesthetized rats. This is the first report presenting the protective effect of Na+/H+ exchange inhibitors on isoproterenol- or vasopressin-induced ECG changes in rats, providing the future perspective of SMP-300, a potent Na+/H+ exchange inhibitor, as an anti-anginal drug.