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

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Abstract
(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 inhibitiors 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 μmol/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 μmol/l, respectively). Zaprinast and rolipram preferentially inhibited PDE I and II, respectively. IBMX and AR-L 57 Cl inhibited PDE I-111 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 μmol/l and 6.0 μmol/l, respectively. Milrinone exerted a biphasic increase in force of contraction with EC5o values of 0.2 and 695 μmol/l. These substances which selectively inhibited PDE III increased force of contraction maximally by 2.04 mN (UD-CG 212 Cl), 2.77 mN (pimobendan) and 3.29 mN (milrinone). Milrinone increased the frequency of beating by 40%, pimobendan by 22% and UD-CG 212 Cl by 16% at maximal positive inotropic concentrations. (4) The unselective PDE I-III inhibitors IBMX and AR-L 57 Cl increased force of contraction with the highest maximal effects (5.9 mN and 4.23 mN, respectively). There was no correlation between EC5o values for the positive inotropic effects and IC50 values for the inhibition of PDE I–III. Zaprinast exerted only weak (0.87 mN) and rolipram no effects on force of contraction. The latter substances had no positive chronotropic effects. (5) In conclusion, the positive inotropic effects of the new cardiotonic agents pimobendan, UD-CG 212 Cl and milrinone may be at least in part due to selective cardiac PDE III inhibition. For UD-CG 212 Cl and pimobendan the IC50 for PDE III inhibition and the EC50 for the positive inotropic effects were of the same order of magnitude. For milrinone, only the lower EC50 value is similar to the IC50 for the inhibition of PDE III. In the case of the unselective PDE III inhibitors IBMX and AR-1. 57 Cl a factor of 20 was found between potencies for positive inotropy and PDE III inhibition. Thus, PDE III inhibition seems to be a prerequisite for PDE inhibition as a mechanism of action for increasing force of contraction. However, the pronounced positive inotropic effects of IBMX and AR-L 57 Cl provide evidence that a selectivity for PDE III inhibition seems not to be essential for increasing force of contraction. Finally, there is no indication that inhibition of PDE I or II plays a major role in increasing force of contraction.