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

The effects of 6,7,8,9-tetrahydro-2-methyl-5 H-cyclohepta[ b]pyridine-3-carbonylguanidine maleate (TY-12533) on myocardial ischemia/reperfusion injury were evaluated in rats. Inhibitory effects of TY-12533, TY-50893 (the 9-chloro 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 ischemia (0.03–0.1 mg/kg, i.v.) and during ischemia (0.1–1 mg/kg) on the ischemia/reperfusion-induced myocardial infarction. These differences between TY-12533 and the other drugs in vitro and in vivo may be ascribed to the p K a values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).