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 micrograms/kg/min i.v., n = 6) and ouabain (40 micrograms/kg i.v., n = 4), measurements were performed during normoperfusion in additional animals. Under normal conditions, either Na(+)-channel activator induced increases in dP/dtmax (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/dtmax 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/dtmax 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/dtmax 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Pathophysiology, University of Essen Medical School, FRG.
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Baumgart
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Ehring
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Krajcar
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Skyschally
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Heusch
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000502:physiology; D001384:Azetidines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D007536:Isomerism; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D001384:Azetidines; D002316:Cardiotonic Agents; D010879:Piperazines; D015222:Sodium Channels; C071117:BDF 9148; D010042:Ouabain; C046261:DPI 201-106; D009638:Norepinephrine