Aihara K, Hisa H, Sato T, Yoneyama F, Sasamori J, Yamaguchi F, Yoneyama S, Mizuno Y, Takahashi A, Nagai A, Kimura T, Kogi K, Satoh S
Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, 980-8578, Sendai, Japan.
Eur J Pharmacol. 2000 Sep 15;404(1-2):221-9. doi: 10.1016/s0014-2999(00)00613-0.
The effects of 6,7,8, 9-tetrahydro-2-methyl-5H-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 pK(a) values of the guanidinium moiety of TY-12533 (6.93), TY-50893 (6.35) and cariporide (6.28).
在大鼠中评估了6,7,8,9 - 四氢 - 2 - 甲基 - 5H - 环庚并[b]吡啶 - 3 - 羰基胍马来酸盐（TY - 12533）对心肌缺血/再灌注损伤的影响。在体外，TY - 12533、TY - 50893（TY - 12533的9 - 氯衍生物）和卡立泊来德对血小板Na(+)/H(+)交换体的抑制作用在pH 6.2时几乎相等，在pH 6.7时降低；但在pH 6.7时，TY - 12533的效力是TY - 50893和卡立泊来德的四倍。在缺血前静脉注射（0.01 - 1 mg/kg）TY - 12533、TY - 50893和卡立泊来德在体内对缺血/再灌注诱导的心律失常的抑制程度相同；但在缺血期间（0.1 - 1 mg/kg）给药时，TY - 12533比卡立泊来德和TY - 50893更有效。对于这些药物在缺血前（0.03 - 0.1 mg/kg，静脉注射）和缺血期间（0.1 - 1 mg/kg）给药对缺血/再灌注诱导的心肌梗死的抑制作用，也得到了类似的结果。TY - 12533与其他药物在体外和体内的这些差异可能归因于TY - 12533（6.93）、TY - 50893（6.35）和卡立泊来德（6.28）胍基部分的pK(a)值。
