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, alpha- and beta-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 mu g/ kg/min i.v., n = 6) and ouabain (40 mu g/kg i.v., n = 4), measurements were performed during normoperfusion in additional animals. Under normal conditions, either Na+-channel activator induced increases in dP/dt(max) (lower dosage: 45-84%, higher dosage: by 93-117%) and AWT (lower dosage: by 24-37%, higher dosage: by 19-56%). Under ischemic conditions, either drug increased dP/dt(max) by 60-98% and AWT by 45-102%. Excitability, conduction times, and refractory period did not change significantly in response to the Na+-channel activators, neither under normal nor under ischemic conditions. There was no significant difference in the incidence of spontaneous ventricular extrasystoles before and after administration of either Na+-channel activator. In contrast, an equi-inotropic dosage of norepinephrine (increases in dP/dt(max) by 148% and AWT by 42%) increased excitability, decreased conduction times and refractory period, and increased the incidence of spontaneous ventricular extrasystoles. Ouabain induced only a moderate increase in dP/dt(max) by 56% and AWT by 24%, but elicited sustained and complex ventricular arrhythmias. Excitability was markedly increased, whereas conduction times and refractory period changed only little. The present study demonstrated that the three Na+-channel activators exert a profound positive inotropic action with little intrinsic arrhythmogenic action under normal and ischemic conditions.