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

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)

Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

“…Studies in vivo have also shown that Na ϩ channel enhancers increase cardiac contractile performance in anesthetized dogs with acute ischemia (Baumgart et al, 1994) and in the chronic microembolization-induced failing heart model (Taniumra et al, 2000). However, no prior study has systematically investigated the effect of a Na ϩ channel enhancer on hemodynamic and cardiac function in the conscious animal with heart failure.…”

“…It has also been reported that inotropic agents that increase cellular calcium may act centrally to increase vagal tone in dogs with heart failure . Interestingly, the negative cardiac chronotropic response to LY341311 was not found in normal dogs, either under anesthetic (Baumgart et al, 1994) or fully conscious (Gill et al, 2002). It is well known that heart failure is associated with derangements of autonomic control of the cardiovascular system, manifested as reduced parasympathetic activity and elevated sympathetic activity (Kinugawa and Dibner-Dunlap, 1995;Wang et al, 1999).…”

“…Sodium channel enhancers have been shown to elicit positive inotropic effects in isolated cardiac tissues from experimental animals and from human papillary muscles obtained from normal as well as failing hearts (Flesch et al, 1996;Schwinger et al, 1996;Mü ller-Ehmsen et al, 1997). These compounds also improve left ventricular contractile function in anesthetized dogs with either normal (Baumgart et al, 1994) or failing hearts (Taniumra et al, 2000). …”

First Report on an Inotropic Peptide Activating Tetrodotoxin-Sensitive, “Neuronal” Sodium Currents in the Heart

“…Activators of the main cardiac sodium channel Nav 1.5 increase contractility. 5,22 Activation of Nav 1.5 , however, also prolongs repolarization 5,22 and provokes ventricular arrhythmias. 23 Tetrodotoxin-sensitive sodium channels contribute to sodium influx and increased contractility in the heart: Approximately 25% of mammalian cardiac sodium channels are tetrodotoxin sensitive, and preferentially localized close to the T tubules.…”

“…4 Activators of cardiac sodium channels are known to not only exert positive inotropic effects but also cause arrhythmias. 5 Cardiac sodium channels can be divided into tetrodotoxin-resistant (µmol/L range) and tetrodotoxin-sensitive (nmol/L range) channel subtypes. 4 The main isoform of the tetrodotoxin-resistant sodium channels Nav 1.5 is expressed predominantly in cardiomyocytes.…”