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

Basic Res Cardiol. Jan-Feb 1994;89(1):61-79. doi: 10.1007/BF00788678.

Abstract

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)

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aorta / physiology
  • Azetidines / pharmacology*
  • Blood Pressure / drug effects
  • Cardiotonic Agents / pharmacology*
  • Dogs
  • Electric Stimulation
  • Electrocardiography / drug effects
  • Heart Rate / drug effects*
  • Hemodynamics / drug effects*
  • Isomerism
  • Myocardial Contraction / drug effects*
  • Norepinephrine / pharmacology
  • Ouabain / pharmacology
  • Piperazines / pharmacology*
  • Regional Blood Flow / drug effects
  • Sodium Channels / drug effects
  • Sodium Channels / physiology*
  • Vascular Resistance / drug effects
  • Ventricular Function, Left / drug effects

Substances

  • Azetidines
  • Cardiotonic Agents
  • Piperazines
  • Sodium Channels
  • BDF 9148
  • Ouabain
  • DPI 201-106
  • Norepinephrine