Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action.
OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]- 2(1H)-quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and decreased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10(-6) to 10(-4) M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dose-dependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by beta-blockade. OPC-18790 (10(-5) to 10(-4) M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K(+)-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 x 10(-6) M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.
Hosokawa
T
T
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., Japan.
Mori
T
T
Fujiki
H
H
Kinoshita
S
S
Takemoto
K
K
Imaizumi
T
T
Noda
T
T
Ohura
M
M
Tominaga
M
M
Yabuuchi
Y
Y
D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects
D002316:Cardiotonic Agents; D015363:Quinolones; C077543:toborinone