Itoh S, Mori T, Yoshida K, Fujiki H, Tominaga M, Yabuuchi Y
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Japan.
Jpn J Pharmacol. 1995 Nov;69(3):229-37. doi: 10.1254/jjp.69.229.
OPC-18790, (+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quin olinone, is a novel positive inotropic agent, and its mechanism of positive inotropic action involves not only phosphodiesterase inhibition, but also a prolongation of action potential duration in ventricular muscle. Prolongation of action potential duration is also a property of class III antiarrhythmic agents; therefore, we examined the cardiohemodynamic effects and arrhythmogenicity of a combination of OPC-18790 and dopamine in halothane-anesthetized dogs. Dopamine (5 micrograms/kg/min) alone increased the peak of the first derivative of left ventricular pressure (LVdP/dtmax) and cardiac output (CO) by 43-48% and 16-20%, respectively, while OPC-18790 (10 micrograms/kg/min) increased these parameters by 56% and 22%, respectively. The combination of OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) and dopamine alone at an increased dose of 10 micrograms/kg/min further increased LVdP/dtmax and CO by 104-113% and 29-30%, respectively. Thus, positive inotropic effects were equally observed in both groups, and the effects of OPC-18790 and dopamine seemed to be additive. The other hemodynamic effects were similar among all groups. Arrhythmias such as premature ventricular contraction developed in 5 out of 7 dogs (71.4%) in the 10-micrograms/kg/min dopamine group, while only one premature ventricular contraction was observed in 1 of 7 dogs (14.3%) in the OPC-18790 (10 micrograms/kg/min) and dopamine (5 micrograms/kg/min) combination group. These results suggest that the combination of OPC-18790 and dopamine may provide new therapeutic options for the treatment of heart failure.
OPC - 18790，（±）-6 - [3 - （3,4 - 二甲氧基苄基氨基）-2 - 羟基丙氧基]-2（1H）-喹啉酮，是一种新型的正性肌力药物，其正性肌力作用机制不仅涉及磷酸二酯酶抑制，还包括心室肌动作电位时程的延长。动作电位时程的延长也是Ⅲ类抗心律失常药物的特性；因此，我们研究了在氟烷麻醉犬中OPC - 18790与多巴胺联合应用的心脏血流动力学效应和致心律失常性。单独使用多巴胺（5微克/千克/分钟）可使左心室压力一阶导数峰值（LVdP/dtmax）和心输出量（CO）分别增加43 - 48%和16 - 20%，而OPC - 18790（10微克/千克/分钟）分别使这些参数增加56%和22%。OPC - 18790（10微克/千克/分钟）与多巴胺（5微克/千克/分钟）联合应用以及单独使用剂量增加至10微克/千克/分钟的多巴胺，可使LVdP/dtmax和CO分别进一步增加104 - 113%和29 - 30%。因此，两组均观察到同等的正性肌力作用，且OPC - 18790和多巴胺的作用似乎具有相加性。所有组的其他血流动力学效应相似。在10微克/千克/分钟多巴胺组的7只犬中有5只（71.4%）出现室性早搏等心律失常，而在OPC - 18790（10微克/千克/分钟）与多巴胺（5微克/千克/分钟）联合应用组的7只犬中有1只（14.3%）仅观察到1次室性早搏。这些结果表明，OPC - 18790与多巴胺联合应用可能为心力衰竭的治疗提供新的治疗选择。
