HIGH SELECTIVITY FOR INHIBITION OF PHOSPHODIESTERASE-III AND POSITIVE INOTROPIC EFFECTS OF MCI-154 IN GUINEA-PIG MYOCARDIUM

MCI-154 (0.3-100 muM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 muM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI-154. In intact contracting papillary muscles, the positive inotropic effect was accompanied by an increase in cyclicAMP content to 0.78 +/- 0.09 pmol/mg wet weight (n = 10), corresponding to 150% of the basal value (0.51 +/- 0.05 pmol/mg wet weight, n = 21) in the presence of submaximal cyclicAMP phosphodiesterase (PDE) isoenzyme III inhibiting concentrations of MCI-154 (30 muM). MCI-154 (1-1,000 muM) concentration-dependently inhibited the activity of PDE III from homogenates of guinea pig myocardium. The IC50 was 3.8 muM. PDE I, II, and IV were not significantly affected up to 100 muM (PDE I and IV) and up to 1,000 muM (PDE II). In comparison, milrinone and saterinone were PDE III/IV-selective PDE inhibitors. Rolipram inhibited PDE IV only. IBMX and theophylline were nonselective PDE inhibitors. MCI-154 had only a marginal positive chronotropic effect. The frequency of spontaneously beating fight auricles from guinea pig heart was increased by 8.7% at most (n = 5). MCI-154 increased Ca2+ sensitivity in chemically skinned porcine ventricular muscle fibers. FOC was maximally enhanced to 129.3% of control value by MCI-154 (100 muM). The positive inotropic effect of MCI-154 is probably due mainly to inhibition of PDE III. In contrast to the PDE III/IV-selective PDE inhibitors milrione and saterinone, MCI-154 inhibited PDE III only. The increase in Ca2+ sensitivity of the contractile proteins by MCI-154 may contribute to the positive inotropic effect.