Cardioprotective effect of TY-12533, a novel Na+/H+ exchange inhibitor, onischemia/reperfusion injury

The effects of 6,7,8,9-tetrahydro-2-methyl-5H-cyclohepta[b]pyridine-3-carbo nylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury w ere evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chlo ro derivative of TY-12533) and cariporide on the platelet Na+/H+ exchanger in vitro were almost equal at pH 6.2 and decreased at pH 6.7; but TY-12533 was four times more potent than TY-50893 and cariporide at pH 6.7. TY-12533 , TY-50893 and cariporide administered before ischemia (0.01-1 mg/kg, i.v.) suppressed the ischemia/reperfusion-induced arrhythmias to the same extent in vivo; but TY-12533 was more effective than cariporide and TY-50893 when they were administered during ischemia (0.1-1 mg/kg). Similar results were obtained for the inhibitory effects of these drugs administered before isc hemia (0.03-0.1 mg/kg, i.v.) and during ischemia (0.1-1 mg/kg) on the ische mia/reperfusion-induced myocardial infarction. These differences between TY -12533 and the other drugs in vitro and in vivo may be ascribed to the pK(a ) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28). (C) 2000 Elsevier Science B.V. All rights reserved.