Wettwer E, Himmel H, Ravens U
Department of Pharmacology, University of Essen, Germany.
Pharmacol Toxicol. 1992 Aug;71(2):95-102. doi: 10.1111/j.1600-0773.1992.tb00526.x.
The amiloride derivatives, 2',3'-benzobenzamil (BB), 3',4'-dichlorobenzamil (DCB), and 5-(N-4-chlorobenzyl)-2',4'-dimethylbenzamil (CBDB) are known as inhibitors of the Na+/Ca2+ exchange. This kind of drug action was recently suggested to be a new inotropic mechanism. In guinea-pig myocardium, we have studied the inotropic and the accompanying electrophysiological effects of the three compounds in order to assess their selectivity of action. In left atria and in papillary muscle, force of contraction increased with DCB and CBDB (atria only) at a high concentration (5 x 10(-5)-10(-4) mol/l) and after long exposure time, whereas BB produced a negative inotropic effect. In the isolated perfused Langendorff heart, the amiloride derivatives tested decreased spontaneous heart rate and force of contraction and prolonged the duration of contraction. In isolated cardiac myocytes, sodium current, calcium current and the delayed rectifier were reduced by concentrations of BB, DCB and CBDB similar to the IC50 values reported for the inhibition of the Na+/Ca2+ exchange. Our results demonstrate that the amiloride derivatives have multiple sites of action. It is concluded that more specific modulators of the Na+/Ca2+ exchange are required in order to define their contribution to the regulation of contractile activation of the heart.
氨氯吡脒衍生物，2'，3'-联苯氨氯吡脒（BB）、3'，4'-二氯氨氯吡脒（DCB）和5-（N-4-氯苄基）-2'，4'-二甲基氨氯吡脒（CBDB）是已知的Na+/Ca2+交换抑制剂。最近有人提出这种药物作用是一种新的变力机制。在豚鼠心肌中，我们研究了这三种化合物的变力作用及伴随的电生理效应，以评估它们的作用选择性。在左心房和乳头肌中，高浓度（5×10(-5)-10(-4)mol/L）且长时间暴露后，DCB和CBDB（仅心房）可使收缩力增加，而BB则产生负性变力作用。在离体灌注的Langendorff心脏中，所测试的氨氯吡脒衍生物可降低自发心率和收缩力，并延长收缩持续时间。在离体心肌细胞中，BB、DCB和CBDB的浓度降低了钠电流、钙电流和延迟整流电流，其浓度与报道的抑制Na+/Ca2+交换的IC50值相似。我们的结果表明，氨氯吡脒衍生物有多个作用位点。结论是，需要更特异性的Na+/Ca2+交换调节剂来确定它们对心脏收缩激活调节的贡献。
