Cardiovascular effects of the combination of OPC-18790 and dopamine in halothane-anesthetized dogs.
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.
Itoh
S
S
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Japan.
Mori
T
T
Yoshida
K
K
Fujiki
H
H
Tominaga
M
M
Yabuuchi
Y
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004298:Dopamine / Q000494:pharmacology*; D004338:Drug Combinations; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D015363:Quinolones / Q000494:pharmacology*; D013997:Time Factors
D002316:Cardiotonic Agents; D004338:Drug Combinations; D015363:Quinolones; C077543:toborinone; D006221:Halothane; D004298:Dopamine