Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), in the dog with and without beta-blocker and Ca++-antagonist pretreatment.
Hemodynamic effects of a new inotropic agent, OPC-8212 (2(1H)-quinolinone derivative) were studied in anesthetized open chest dogs pretreated with propranolol and diltiazem. Three doses (1, 3 and 10 mg/kg) of OPC-8212 were administered intravenously and the net hemodynamic effect (% change) was obtained by subtraction of the effect of the solvent from the gross effect, since the vehicle has a transient, but significant hemodynamic effect. The maximal inotropic effect occurred 3 minutes after administration: LV dP/dt max and cardiac output (CO) increased by 19 +/- 2.5% and 28 +/- 8.5%, respectively, at 3 mg/kg. These cardiotonic effects were dose-dependent, whereas heart rate, peak LV pressure (PLVP) and mean aortic pressure were minimally changed at any dose. Accordingly, systemic vascular resistance (SVR) decreased in a dose-dependent manner although the decrease was much less than that in administration of isoproterenol. The inotropic effect was not blocked by beta-adrenoceptor blockade (propranolol 1 mg/kg), indicating that the cardiotonic action of this agent is not due to beta-adrenergic stimulation. Thus, this agent could reverse beta-blocker-induced heart failure. During infusion of diltiazem (0.1 mg/kg/min following bolus intravenous administration of 0.5 mg/kg), the increases in LV dP/dt max and CO due to OPC-8212 were similar to those in the control study. In contrast to the effects under beta-adrenoceptor blockade, however, decreased PLVP was restored by OPC-8212. Neither chronotropic nor rrhythmogenic effects were observed in the control or with either pharmacological intervention. These results indicate that OPC-8212 has a potent inotropic action with modest vasodilatory effect even with propranolol or diltiazem pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
M
M
Hori
M
M
Inoue
J
J
Tamai
Y
Y
Koretsune
M
M
Kitakaze
K
K
Iwai
H
H
Ito
A
A
Kitabatake
T
T
Kamada
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D001552:Benzazepines; D002316:Cardiotonic Agents; D014677:Pharmaceutical Vehicles; D011719:Pyrazines; D011804:Quinolines; D013876:Thiophenes; C041667:vesnarinone; D004110:Diltiazem; D007545:Isoproterenol; C013693:sulfolane