Relation of positive inotropic and chronotropic effects of pimobendan, UD-CG 212 Cl, milrinone and other phosphodiesterase inhibitors to phosphodiesterase III inhibition in guinea-pig heart.

(1) This study was performed to elucidate the relation between positive inotropy and phosphodiesterase inhibition in the heart. Therefore, the influence on the activity of guinea-pig cardiac phosphodiesterase (PDE) I-III separated by DEAE-cellulose anion exchange chromatography was investigated for the new cardiotonic agents pimobendan, its metabolite UD-CG 212 Cl and milrinone. These effects were compared with those of various other PDE inhibitors such as IBMX, zaprinast, rolipram and AR-L 57 Cl. A selectivity factor (SF, mean of the IC50 values for PDE I and II inhibition divided by the IC50 for PDE III) was calculated for each drug. The greater this value the more selective was the PDE III inhibition. (2) UD-CG 212 Cl was the most potent (IC50 = 0.19 mumol/l) and most selective inhibitor of PDE III with a SF of 869. Also selective PDE III inhibitors were pimobendan (SF = 50.5) and milrinone (SF = 70.0) with slightly smaller potencies (IC50 = 2.40 and 1.52 mumol/l, respectively). Zaprinast and rolipram preferentially inhibited PDE I and II, respectively. IBMX and AR-L 57 Cl inhibited PDE I-III unselectively with similar potencies for all isoenzymes. (3) The PDE inhibitory effects of all substances were compared with their influence on force of contraction (electrically driven papillary muscles) and on frequency of beating (spontaneously beating right auricles) in guinea-pig hearts, thus in preparations of the same species. UD-CG 212 Cl and pimobendan resembled each other in their maximal positive inotropic effects with potencies (EC50) of 1.8 mumol/l and 6.0 mumol/l, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective inhibition of cAMP phosphodiesterase III activity by the cardiotonic agent saterinone in guinea pig myocardium.

The effects of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy] phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) on force of contraction, beating frequency, and on phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. Saterinone exerted a concentration-dependent (1-30 mumol/l) positive inotropic effect (EC50 = 9.1 mumol/l) in guinea pig papillary muscles. The drug was more potent in increasing force of contraction than was milrinone, but its efficacy was only half as great as that of milrinone. Also IBMX revealed an about 4-fold greater positive inotropic efficacy than saterinone. This study provides functional evidence that the positive inotropic effect of saterinone is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction completely. In order to elucidate a possible mechanism of action of saterinone its effects on cardiac cAMP PDE activity were investigated. Saterinone selectively and potently inhibited the isoenzyme III of PDE (IC50 = 0.06 mumol/l). The mean IC50-values for the inhibition of PDE I and II were 323-fold greater. Thus, saterinone proved to be a selective inhibitor of "low-Km, cAMP specific" PDE III. Saterinone revealed only a moderate positive chronotropic effect. The beating frequency of guinea pig spontaneously beating right auricles was augmented by 26.4% at most, that is half as much as the effect of isoprenaline at a similarly effective positive inotropic concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of action and cardiotonic activity of a new phosphodiesterase inhibitor, the benzimidazole derivative adibendan (BM 14.478), in guinea-pig hearts.

1. The effects of adibendan (BM 14.478; 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f] benzimidazole-6-one) on force of contraction and beating frequency were analysed in guinea-pig electrically driven papillary muscles and spontaneously beating right auricles, respectively. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. 2. Adibendan exerted a concentration-dependent (0.03-300 mumol/l) positive inotropic effect in papillary muscles (EC50 = 1.3 mumol/l) which was only partially reversible. The efficiency of adibendan was less than that of milrinone, but adibendan was about two orders of magnitude more potent and had only slight positive chronotropic effects (113% of pre-drug values) at most. Milrinone increased the frequency of beating maximally to 140% of pre-drug values. The positive inotropic effect of adibendan is probably at least partially mediated by cAMP since carbachol reduced the increase in force of contraction by about 75%. 3. To elucidate the mechanism of action of adibendan we investigated its effects on phosphodiesterase I-III and adenylate cyclase activity in isolated preparations from guinea-pig hearts. 4. Adibendan selectively inhibited phosphodiesterase III (PDE III) activity concentration-dependently (IC50 = 2.0 mumol/l). The IC50 values for the inhibition of PDE I or II were more than 60-fold higher. Since adibendan did not affect adenylate cyclase activity a stimulation of the cAMP synthesis as a mechanism of action can be ruled out. 5. The results provide evidence that the positive inotropic action of adibendan is at least in part due to an inhibition of cAMP-PDE III.(ABSTRACT TRUNCATED AT 250 WORDS)