Cardiac and hemodynamic effects of intravenous R 80122, a new phosphodiesterase III inhibitor, in anesthetized and awake dogs.
R 80122 is a newly synthesized, selective phosphodiesterase III inhibitor. The cardiac and hemodynamic effects of this compound following intravenous administration were studied in closed-chest anesthetized as well as in conscious chronically instrumented dogs. The findings in the closed-chest anesthetized dogs indicate that R 80122 has positive inotropic and possibly moderate vasodilating properties [maximum increase in LV dp/dtmax/pd: 61%, and maximum decrease in systemic vascular resistance: 29% (a 12.5% decrease for the solvent)]. As a result, cardiac output maximally increased to 149% of the control value. The most striking effect of R 80122 was its positive lusitropic effect (maximal decrease in the time constant of relaxation [T] of 46%). This pronounced lusitropic effect of R 80122 can be regarded as beneficial, because of the increasing evidence that lusitropic defects play an important role in disorders related to heart failure. These effects of R 80122 were associated with only slight changes in arterial blood pressure. The effects of R 80122 lasted about 75 min after stopping the infusion. No ventricular arrhythmias were noted during and after infusion of the compound. The positive inotropic effects seen in anesthetized dogs were confirmed in conscious nonsedated dogs. It may be concluded that R 80122 has a clinically favorable cardiovascular profile for acute applications in heart failure, because its combined positive inotropic and positive lusitropic effects, and moderate vasodilating properties lead to a pronounced increase in cardiac output and only minimal changes in aortic blood pressure.
Van de Water
A
A
Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
d'Aubioul
J
J
Van Gerven
W
W
de Chaffoy de Courcelles
D
D
Freyne
E
E
Xhonneux
R
R
Reneman
R S
RS
Janssen
P A
PA
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; C076518:R 80122