Electropharmacologic effects of a new phosphodiesterase III inhibitor, toborinone (OPC-18790), assessed in an in vivo canine model.
Electropharmacologic effects of a new phosphodiesterase (PDE) III inhibitor toborinone (OPC-18790) were assessed in a halothane-anesthetized, closed-chest canine model. Toborinone, 0.03 mg/kg, increased ventricular contractility, decreased total peripheral resistance, and inhibited intraventricular conduction without changing other cardiovascular parameters. A clinically relevant dose of 0.3 mg/kg increased heart rate, systolic blood pressure, and cardiac output, decreased preload to the left ventricle, enhanced atrioventricular nodal conduction, and shortened repolarization and the vulnerable period of the ventricle, in addition to enhancing the effects observed after the low dose. A high dose of 3 mg/kg of toborinone decreased systolic, mean, and diastolic pressures and prolonged the effective refractory period (ERP) in addition to the effects observed after the middle dose. No further change was detected in ventricular repolarization. Most of the cardiohemodynamic effects can be explained by the PDE III inhibition by toborinone. With regard to electrophysiologic properties, the prolongation of intraventricular conduction time and ERP by toborinone suggests sodium channel inhibition. The lack of the prolongation of ventricular repolarization suggests that previously demonstrated inhibition of I(Kr) and I(K1) and increased I(Ca-L) by toborinone might be counteracted by factors such as the cyclic AMP-dependent outward currents, I(Ks) and I(C1).
Sugiyama
A
A
Department of Pharmacology, Yamanashi Medical University, Japan. atsushis@res.yamanashi-med.ac.jp
Satoh
Y
Y
Hashimoto
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; C077543:toborinone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3