INVESTIGATIONS OF THE MECHANISM OF THE POSITIVE INOTROPIC ACTION OF BDF-9148 - COMPARISON WITH DPI-201-106 AND THE ENANTIOMERS

The electromechanical and biochemical activities of the positive inotr opic compounds BDF 9148 and DPI 201-106 were compared in guinea-pig my ocardic preparations. Additionally, the properties of the BDF 9148 ena ntiomers were studied to compare their positive inotropic effects. In guinea pig papillary muscles, BDF 9148 exerted a concentration-depende nt increase of force of contraction with a 50% effective concentration (EC(50)) value of 0.6 mu M, compared with 1.3 mu M for DPI 201-106. L ike that of DPI, the inotropic effect of BDF 9148 was abolished by tre atment with tetrodotoxin (TTX) but not affected by treatment with carb achol. Likewise, pretreatment of the papillary muscles with propranolo l, cimetidine, and histamine did not affect the contractile effects of BDF 9148. In the left atria, both agents had a positive inotropic eff ect with an EC(50) of 0.2 mu M for BDF and 0.8 mu M for DPI. Incubatio n of single concentrations of the respective drugs for a period of 90 min with guinea pig papillary muscles resulted in slightly differing p arameters of isometric contraction. in contrast to DPI, BDF 9148 prolo nged the contraction time transiently. Time to peak force was not mark edly influenced by either drug. The functional refractory period was p rolonged by both drugs to a similar extent. At 10 mu M, BDF 9148 showe d a biphasic effect on the action potential duration (APD) most eviden t at APD(90), whereas DPI prolonged APD(90) 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 mu scle.