title: In vitro pharmacology of R 80122, a novel phosphodiesterase inhibitor.
abstract: The cardiac in vitro effects of R 80122, a novel phosphodiesterase (PDE) inhibitor, were investigated and compared with those of the reference compound milrinone and of the calcium-sensitizer adibendan. In guinea pig left atria, both milrinone and R 80122 increased contractile force; 10 microM milrinone was equieffective to 1 microM R 80122. The rate of spontaneously beating atria was not altered by R 80122 in the concentration range of 0.01-0.3 microM. Higher concentrations (1-10 microM) led to a statistically insignificant increase of 20%. Milrinone's effect on frequency was more pronounced and amounted to 21% at 10 microM and to 40% at 100 microM. Adibendan increased heart rate (HR) by 10% at a concentration of only 0.03 microM. This effect was not enhanced any further by increasing the concentration. In papillary muscle, the positive inotropic effects of both milrinone and R 80122 were inhibited by carbachol, indicating involvement of cyclic AMP. Further indications for a cyclic AMP-dependent action were obtained by induction of slow action potentials and synergism with isoprenaline. In electrophysiologic measurements, milrinone reduced action potential duration (APD) in a high concentration whereas R 80122 had no effect. Action potential changes elicited by a toxic concentration of ouabain were reduced by R 80122. Relaxation of rat aortic rings contracted by KCl and relaxation of guinea pig aortic rings contracted by norepinephrine (NE) was comparable for both milrinone and R 80122. R 80122 also caused relaxation of canine coronary arteries constricted with prostaglandin F2 alpha (PGF2 alpha) both with and without endothelium. NE-induced contractions in canine gastrosplenic arteries were not affected by R 80122. Cardiac contractility that had been impaired to various degrees by pentobarbital or by aging was restored to control values by both milrinone and R 80122. R 80122 enhanced cardiac contractility at lower concentrations than milrinone with no concomitant increase in frequency or shortening of the action potential, which may be advantageous for treatment of heart failure.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D000078183:Oxindoles; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D000078183:Oxindoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011799:Quinazolines; D014665:Vasodilator Agents; C076518:R 80122; D010042:Ouabain; D002217:Carbachol; C053007:adibendan; D020105:Milrinone; D007545:Isoproterenol; D009638:Norepinephrine