Effect of SMP-300, a new Na+/H+ exchange inhibitor, on myocardial ischemiaand experimental angina models in rats

We evaluated the effects of SMP300 (N-(aminoiminomethyl)-11-chloro-5,6,7,8- tetrahydro-8-oxo-4H-pyrrolo[3,2, 1-kl] [1]benzazocine-2-carboxamide monomet hanesulfonate monohydrate), a newly synthesized compound, on Na+/H+ exchang e activity in rat cardiomyocytes and on other ion transporters, channels an d receptors. We also investigated the protective effects of SMP-300 in isol ated ischemic rat hearts and rat isoproterenol- or vasopressin-induced expe rimental angina models. SMP-300 concentration-dependently inhibited recover y from acidosis in rat myocytes, and its IC50 for Na+/H+ exchange was 6 nM. In comparison, its IC(50)s for Na+/Ca2+ exchange and for the Na+ channel w ere >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), administer ed only at preischemia and not during reperfusion, significantly improved t he 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 isop roterenol-induced ST-segment depression in the ECG of anesthetized rats, in a dose-dependent manner. SMP300 (0.1 mg/kg, i.v.) and 5-(N-ethyl-N-isoprop yl)-amiloride (1 mg/kg, i.v.) also inhibited the vasopressin-induced ST-seg ment depression in the ECG of anesthetized rats. This is the first report p resenting the protective effect of Na+/H+ exchange inhibitors on isoprotere nol- or vasopressin-induced ECG changes in rats, providing the future persp ective of SMP-300, a potent Na+/H+ exchange inhibitor, as an anti-anginal d rug.