Differing electrophysiological effects of class IA, IB and IC antiarrhythmic drugs on guinea‐pig sinoatrial node

Campbell, Terence J.

doi:10.1111/j.1476-5381.1987.tb10294.x

Cited by 10 publications

(3 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other Ic antiarrhythmic agents such as flecainide, which also prolong AV conduction and refractoriness (e.g. Hodess et al, 1979), have been shown to influence potassium currents (Follmer & Colasky, 1990) whereas lb drugs which do not slow conduction during normal sinus rhythm have no such effect at therapeutic concentrations (Campbell, 1987). These in vitro effects may explain the lengthening of the AV nodal refractory period observed in this study.…”

Section: Discussionmentioning

confidence: 58%

Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog

Leboeuf¹,

Basiez²,

Massingham³

1993

British J Pharmacology

View full text Add to dashboard Cite

1 The intravenous electrophysiological effects of a new antifibrillatory agent, Org 7797, were studied in closed chest anaesthetized dogs. Effects of fast sodium and slow calcium-mediated action potentials were also examined in guinea-pig isolated papillary muscle. 2 The major effects of a known antifibrillatory dose of Org 7797 (0.5 mg kg-') were a protracted slowing of AV nodal conduction (for at least 20 min) and prolongation of the AV nodal functional refractory period. Conduction in the atria and His-Purkinje system (reflected by the St-A and HV intervals) were not significantly modified whilst ventricular conduction (reflected by the QRS interval) and the ventricular functional refractory period were only transiently prolonged. No other electrophysiological changes were seen.3 A higher dose of Org 7797 (1.5 mg kg-') slowed conduction at all levels of the myocardium (as evidenced by increases in the St-A, AH, HV and QRS intervals), slightly shortened cardiac repolarization (as assessed from JTc) and decreased Wenckebach rate. Atrial refractory periods were increased whereas effects on ventricular refractory periods were modest. 4 Neither heart rate nor sinus node recovery time were modified by either dose of Org 7797. 5 Org 7797, at a concentration (20 tLM) which reduced Vmax of fast sodium-mediated action potentials in isolated papillary muscle by 83%, did not modify Vma, of slow calcium-mediated action potentials. It prolonged duration of the latter but did not modify that of the former. However, the plateau phase of both the 'fast' and especially the 'slow' action potentials was prolonged. 6 It is concluded that the main electrophysiological effects of a known antifibrillatory dose of Org 7797 in dogs with normal cardiac function are seen at the level of the AV node, actions which are unlikely to be explained by calcium channel block. Higher doses display a class Ic profile. This preferential action on the AV node may contribute to the control of ventricular rate during atrial fibrillation in the absence of infra-nodal conduction disturbances. 7 These results contrast with those previously obtained in infarcted dogs and might further suggest that myocardial infarction enhances the Class I action of Org 7797.

show abstract

Section: Discussionmentioning

confidence: 58%

Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog

Leboeuf¹,

Basiez²,

Massingham³

1993

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…This action would certainly contribute to the lengthening of refractory periods at short cycle lengths. It is of interest in this context that recent reports suggest that all sodium channel blocking agents have the potential to block potassium channels (4,10,13,17) and that the order of selectivity for sodium channel block relative to potassium channel block is Ib > Ic > la. Moreover, both effects may be frequency-dependent (33).…”

Section: J P L a N E U S Et Almentioning

confidence: 99%

Org 7797: A New and Unusual Antiarrhythmic Agent

Planellas¹,

Winslow²,

Yih³

et al. 1992

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Key Words: Antifibrillatory drugs--Cardiac c y c l e a r g 7797.Pharmacological studies have shown that Org 7797 is a potent antifibrillatory agent with additional class Ic antiarrhythmic properties. Its antifibrillatory effects are manifested at the ventricular and supraventricular levels and can be explained by prolongation of wavelength at short cycle lengths leading to the prevention of deterioration of reentrant ventricular tachycardia (VT) to ventricular fibrillation (VF). This appears to result from drug-induced lengthening of refractoriness outweighing slowing of conduction which may, in turn, be a consequence of frequency-dependent prolongation of action potential duration. Org 7797 thus possesses an unusual and interesting electrophysiological profile. Higher doses of the drug are required to prevent or suppress arrhythmias of automatic origin in the dog. The dose required to suppress late ischemia-induced tachycardia, an arrhythmia dependent on sodium channel block for its termination, is four times higher than the dose required to prevent early ischemia-induced VF. Moreover, therapeutic plasma levels of the dose required for suppression of late VT are similar to concentrations required to reduce the maximum rate of depolarization of cardiac cells in vitro. By contrast, in rats plasma levels associated with antifibrillatory activity are much lower, suggesting that the mechanisms underlying the antifibrillatory and antiarrhythmic actions of Org 7797 may be different.In animals with normal hearts and in those with either established or developing infarcts, the hemodynamic effects of intravenous Org 7797 are minimal at antifibrillatory doses. The major effects of Org 7797 in normal animals are a very minor bradycardia (~4 % ) and a modest increase in peripheral vascular resistance, the latter of which was not seen in animals with myocardial infarction. Cardiac contractility and coronary blood flow ~~ ~_ _ _ _ _ _ _ _

show abstract

“…Depression of cardiac pacemaker activity is a common property shared among all class-1 antiarrhythmic agents (1), but it has been questioned if the major action of these drugs, their Na+ channel blocking action, is responsible for the depression, since the Na+ channels contribute little to the pacemaker depolarizations due to the low channel density as well as their inactivation in the range of pacemaker potentials.…”

mentioning

confidence: 99%

Role of the Steady-State Na+ Channel Current in Pacemaker Depolarizations in Young Embryonic Chick Ventricular Myocytes

Sada¹,

Ban²,

Fujita

et al. 1995

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

ABSTRACT-To assess the age-related changes in kinetic properties of the cardiac Na+ channel, whole-cell voltage-clamp (v-c) experiments were conducted using 3-, 10-and 17-day-old embryonic chick ventricular heart cells. In line with the first-order kinetic model, kinetic parameters for the activation and inactivation of the channel were determined from the v-c results. Simulation studies using kinetic parameters so determined have reproduced the current-voltage relations and the steady-state inactivation characteristics observed in cells in the three age groups. The rate of depolarization of the simulated action potentials was also comparable to that experimentally recorded. In conclusion, the steady-state Na+ conductance can play a significant role in the automatic depolarizations observed in young embryonic ventricular cells.Keywords: Heart, Voltage-clamp, Development, Automaticity, Simulation Depression of cardiac pacemaker activity is a common property shared among all class-1 antiarrhythmic agents (1), but it has been questioned if the major action of these drugs, their Na+ channel blocking action, is responsible for the depression, since the Na+ channels contribute little to the pacemaker depolarizations due to the low channel density as well as their inactivation in the range of pacemaker potentials.The fast Na+ channel properties change during development. Above all, the presence of the automatic activities and slow rate of rise of action potential (AP) in ventricular cells is characteristic only in an early stage of development (see ref. 2 for a review). In the previous voltageclamp (v-c) study using cultured heart cells from 3-, 10-and 17-day-old embyronic chick ventricles (3), we quantified the developmental changes in the activation and inactivation kinetics parameters. In the study, we found that the steady-state (window) conductance of the Na+ channel at ca. -40 mV in the young (3-day) heart was 0.6010 of the maximum conductance (gNa), and suggested that the current in this magnitude was large enough to induce the pacemaker depolarization. To provide evidence for the involvement of the window conductance in automatic depolarizations in this tissue, further v-c experiments were carried out for the three age groups, with special reference to the inactivation kinetics over a whole potential range, to enable the simulation study. We report here that the Na+ window current plays an important role in the slow depolarization during the diastole in ventricular cells of young embryos. MATERIALS AND METHODS Experimental proceduresThe hearts from 3-, 10-and 17-day-old chick embryos were dissected under sterile conditions. The procedures for cell separation and cultivation were similar to the previously reported ones (3 -5). The use of fertilized eggs for the v-c experiments was approved and authorized by the Animal Experiment Committee, Yamaguchi University, School of Medicine. Glass pipette electrodes were fabricated by a two-step pulling of Pyrex glass capillary tubes (o.d. =1.4 mm), and each electrode was ...

show abstract

Differing electrophysiological effects of class IA, IB and IC antiarrhythmic drugs on guinea‐pig sinoatrial node

Cited by 10 publications

References 24 publications

Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog

Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog

Org 7797: A New and Unusual Antiarrhythmic Agent

Role of the Steady-State Na+ Channel Current in Pacemaker Depolarizations in Young Embryonic Chick Ventricular Myocytes

Contact Info

Product

Resources

About