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.