Key Points
- Investigate the electromechanical and biochemical mechanisms underlying the positive inotropic effects of BDF 9148, its enantiomers, and DPI 201-106 in myocardial tissue.
- Assessed isometric contractility, refractory period, and action potential duration in isolated guinea-pig papillary muscles and left atria exposed to BDF 9148, DPI 201-106, and BDF enantiomers.
- Tested pharmacological responsiveness against tetrodotoxin, carbachol, propranolol, cimetidine, and histamine.
- Measured myocardial cyclic AMP levels in rat cardiomyocytes and guinea-pig papillary muscles, alongside guinea-pig myocardial Na+/K+-ATPase activity.
- BDF 9148 increased contractile force with an EC50 of 0.6 µM in papillary muscles (vs. 1.3 µM for DPI 201-106) and 0.2 µM in left atria (vs. 0.8 µM for DPI 201-106).
- Inotropic response was fully abolished by tetrodotoxin, unaffected by adrenergic or histamine receptor antagonists, and driven exclusively by the (S-)-enantiomer.
- Neither compound elevated myocardial cyclic AMP or inhibited Na+/K+-ATPase activity at therapeutically active inotropic concentrations.
Structured PICO
PPopulationGuinea-pig myocardic preparations (papillary muscles, left atria) and isolated rat cardiomyocytes
IInterventionBDF 9148 and its enantiomers
OOutcomeForce of contraction (positive inotropic effect)surrogate
BDF 9148 demonstrates a potent, TTX-sensitive positive inotropic effect independent of cAMP elevation and Na+/K+-ATPase inhibition, primarily driven by its (S-)-enantiomer.