Shuji Itoh, Toyoki Mori (*), Kenji Yoshida, Hiroyuki Fujiki, Michiaki Tominaga and Youichi Yabuuchi
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima 771-01, Japan
(*) To whom correspondence should be addressed.
Abstract: OPC-18790, (+-)-6-[3-(3,4-dimethoxybenzylamino)- 2-hydroxypropoxy]- 2(1H)-quinolinone, 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 microg/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 (lO microg/kg/min) increased these parameters by 56% and 22%, respectively. The combination of OPC-18790 (10 microg/kg/min) and dopamine (5 microg/kg/min) and dopamine alone at an increased dose of 10 microg/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 microg/kg/min dopamine group, while only one premature ventricular contraction was observed in 1 of 7 dogs (14.3%) in the OPC-18790 (10 microg/kg/min) and dopamine (5 microg/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.
Keywords: OPC-18790, Positive inotropic agent, Arrhythmogenicity, Dopamine, Halothane
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