Subcellular mechanism of the positive inotropic effect of a new quinolinone derivative OPC-8490 on the dog ventricular myocardium.
OPC-8490 [3,4-dihydro-6-[4-(4-oxo-4-phenylbutyl)-1- piperazinylcarbonyl]-2(1H)-quinolinone citrate] elicited a positive inotropic effect in a concentration-dependent manner on the isolated dog ventricular trabeculae electrically driven at 0.5 Hz in Krebs-Henseleit solution bubbled with 95% O2-5% CO2 at 37 degrees C. The beta-adrenoceptor antagonist, bupranolol (3 x 10(-7) mol/l), did not influence the effect of OPC-8490. The maximal effect of OPC-8490 was 0.19 compared with isoproterenol (1.0). The time course of the increase in contractile force coincided with that of the concomitant cyclic AMP accumulation induced by OPC-8490. The concentration-response curve for the OPC-8490-induced increase in contractile force was superimposable on that of the elevation of cyclic AMP levels. OPC-8490 (10(-5) mol/l) shifted the concentration-response curve for isoproterenol to the left and upward. These results imply that the accumulation of cyclic AMP induced by OPC-8490 through an inhibition of peak III PDE may be responsible for its positive inotropic effect. However, the OPC-8490-induced increase in the contractile force was not abolished by carbachol (3 x 10(-6) mol/l) when the cyclic AMP accumulation caused by the compound was completely inhibited by carbachol. In addition, OPC-8490 did cause a change in the time course of isometric contractions characteristic of cyclic AMP accumulation. These findings indicate that both the cyclic AMP-dependent (peak III PDE inhibition) and the cyclic AMP-independent mechanisms (prolongation of action potential duration by inhibition of K+ conductance) may be involved in the positive inotropic effect of OPC-8490 on the dog ventricular muscle.
Endoh
M
M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Satoh
H
H
Norota
I
I
Hirano
K
K
Hosokawa
T
T
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects*
D002316:Cardiotonic Agents; D010879:Piperazines; D015363:Quinolones; C061380:OPC 8490; D002217:Carbachol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D007545:Isoproterenol