Investigations of the Mechanism of the Positive Inotropic Action of BDF 9148: Comparison with DPI 201-106 and the Enantiomers

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Abstract
The electromechanical and biochemical activities of the positive inotropic compounds BDF 9148 and DPI 201-106 were compared in guinea-pig myocardic preparations. Additionally, the properties of the BDF 9148 enantiomers were studied to compare their positive inotropic effects. In guinea pig papillary muscles, BDF 9148 exerted a concentration-dependent increase of force of contraction with a 50% effective concentration (EC50) value of 0.6 microM, compared with 1.3 microM for DPI 201-106. Like that of DPI, the inotropic effect of BDF 9148 was abolished by treatment with tetrodotoxin (TTX) but not affected by treatment with carbachol. Likewise, pretreatment of the papillary muscles with propranolol, cimetidine, and histamine did not affect the contractile effects of BDF 9148. In the left atria, both agents had a positive inotropic effect with an EC50 of 0.2 microM for BDF and 0.8 microM for DPI. Incubation of single concentrations of the respective drugs for a period of 90 min with guinea pig papillary muscles resulted in slightly differing parameters of isometric contraction. In contrast to DPI, BDF 9148 prolonged the contraction time transiently. Time to peak force was not markedly influenced by either drug. The functional refractory period was prolonged by both drugs to a similar extent. At 10 microM, BDF 9148 showed a biphasic effect on the action potential duration (APD) most evident at APD90, whereas DPI prolonged APD90 progressively until the 90 min. The positive inotropic effect of BDF 9148 could be demonstrated by the (S-), whereas the (R+)-enantiomer was without effect. Neither DPI nor BDF 9148 increased myocardial cyclic adenosine monophosphate (cAMP) in isolated rat cardiomyocytes and guinea pig papillary muscles. Additionally, neither BDF 9148 nor DPI showed an inhibitory effect on the guinea pig myocardic Na+/K(+)-ATP'ase activity in the concentration range with a positive inotropic effect in the guinea-pig papillary muscle.

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