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

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Abstract
Summary 1. The effects of adibendan (BM 14.478; 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-fl 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-l-methylxanthine (IBMX) and milrinone were studied for comparison. 2. Adibendan exerted a concentration-dependent (0.03 –300 μol/l) positive inotropic effect in papillary muscles (EC50 = 1.3 μmol/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 μmol/l). The IC50 values for the inhibition of PDEI 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. However, other mechanisms of action like increased sensitivity of the contractile proteins to Ca2+ may be also involved.