Yamamoto S, Matsui K, Kitano M, Ohashi N
Research Center, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
J Cardiovasc Pharmacol. 2000 Jun;35(6):855-62. doi: 10.1097/00005344-200006000-00005.
We investigated the effect of a newly synthesized compound, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid] on Na+/H+ or Na+/Ca2+ exchange activity in rat cardiomyocytes, and on radioligand binding with several channels or receptors in membrane preparations, and ischemia/reperfusion injury in isolated perfused rat hearts. In myocytes, SM-20550 concentration-dependently inhibited the recovery from acidosis induced by an NH4Cl prepulse in HCO3(-)-free solution. Its IC50 was 10(-8) M, which was 10 times lower than that of ethylisopropyl amiloride (EIPA). SM-20550 (10(-6) M) did not affect the Na+-dependent Ca2+ influx (Na+/Ca2+ exchange activity) in cardiomyocytes. In the radioligand binding assay, SM-20550 did not have affinity for K+ channel, beta-adrenoceptor, adenosine, angiotensin, or endothelin receptors, and had low affinity for Na+ and Ca2+ channels and alpha-adrenoceptors, only at the concentrations of 10(-6)-10(-5) M. In perfused hearts exposed to 40 min of global ischemia and 20 min of reperfusion, SM-20550 (10(-8)-10(-7) M) significantly reduced the elevation of left ventricular end-diastolic pressure during reperfusion, improved the postischemic recovery of developed pressure, and prevented coronary perfusion pressure increase after reperfusion. Furthermore, SM-20550 reduced creatine phosphokinase release during reperfusion and prevented the abnormal gain of tissue Na+ and Ca2+ at the end of reperfusion. These results suggest that SM-20550 is a potent, highly specific Na+/H+ exchange inhibitor, which exerts a protective effect against myocardial ischemia/reperfusion injury. In addition, our data strongly support the hypothesis that Na+/H+ exchange plays an important role in the development of postischemic cardiac dysfunction, most likely by inducing Na+ and Ca2+ overload.
我们研究了一种新合成的化合物SM - 20550 [N -（氨基亚氨基甲基）-1,4 - 二甲基 - 1H - 吲哚 - 2 - 甲酰胺甲磺酸盐]对大鼠心肌细胞中Na⁺/H⁺或Na⁺/Ca²⁺交换活性、对膜制剂中几种通道或受体的放射性配体结合以及对离体灌注大鼠心脏缺血/再灌注损伤的影响。在心肌细胞中，SM - 20550浓度依赖性地抑制了在无HCO₃⁻溶液中由NH₄Cl预脉冲诱导的酸中毒后的恢复。其IC50为10⁻⁸M，比乙基异丙基氨氯吡脒（EIPA）低10倍。SM - 20550（10⁻⁶M）不影响心肌细胞中Na⁺依赖性Ca²⁺内流（Na⁺/Ca²⁺交换活性）。在放射性配体结合试验中，SM - 20550对K⁺通道、β - 肾上腺素能受体、腺苷、血管紧张素或内皮素受体没有亲和力，仅在10⁻⁶ - 10⁻⁵M浓度下对Na⁺和Ca²⁺通道以及α - 肾上腺素能受体有低亲和力。在经历40分钟全心缺血和20分钟再灌注的灌注心脏中，SM - 20550（10⁻⁸ - 10⁻⁷M）显著降低了再灌注期间左心室舒张末期压力的升高，改善了缺血后收缩压的恢复，并防止了再灌注后冠状动脉灌注压的升高。此外，SM - 20550减少了再灌注期间肌酸磷酸激酶的释放，并防止了再灌注结束时组织中Na⁺和Ca²⁺的异常增加。这些结果表明，SM - 20550是一种强效、高度特异性的Na⁺/H⁺交换抑制剂，对心肌缺血/再灌注损伤具有保护作用。此外，我们的数据有力地支持了以下假设：Na⁺/H⁺交换在缺血后心脏功能障碍的发展中起重要作用，很可能是通过诱导Na⁺和Ca²⁺超载。
