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(10-8−10-7M), 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.