Characterization of the inotropic and arrhythmogenic action of the sodium channel activator BDF 9148: a comparison to its S-enantiomer BDF 9196, to its congener DPI 201-106, to norepinephrine, and to ouabain

Positive inotropic substances which enhance the myocardial cAMP level or inhibit the Na+/K+-ATPase are known for their proarrhythmic side-effects. This study was performed to investigate the inotropic and arrhythmogenic action of the Na+-channel activator BDF 9148 (racemate) in comparison to its S-enantiomer BDF 9196, its congener DPI 201-106 (racemate), to norepinephrine, and to ouabain. In 30 open-chest dogs, the effects of these substances on the first derivative of left ventricular pressure (dP/dt, Millar-tip catheter) and anterior systolic wall thickening (AWT, sonomicrometry) were studied. Concomitantly, myocardial excitability, conduction times, and refractory period were assessed with a transmural, three-dimensional, 16-electrode array in the anterior wall. For the study of the Na+-channel activators, α- and β-adrenergic and muscarinic receptors were blocked. A first set of measurements was performed during normoperfusion with administration of BDF 9148 (1 mg/kg, n=8), BDF 9196 (0.5 mg/kg, n=8), and DPI 201-106 (1 mg/kg, n=8), respectively. A second set of measurements was performed with administration of the threefold dosage of either substance. With a severe stenosis on the left anterior descending coronary artery, a final set of measurements was performed, again using the higher dosage of either substance. For the study of norepinephrine (0.5 μg/kg/min i.v., n=6) and ouabain (40 μg/kg i.v., n=4), measurements were performed during normoperfusion in additional animals.