Electrophysiologic Effects of Org 7797, a New Steroidal Antiarrhythmic Agent

Winslow, E.; Martorana, Michael; Bell, Patricia

doi:10.1097/00005344-198908000-00004

Cited by 11 publications

(8 citation statements)

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“…Previous electrophysiological studies in vitro characterized Org 7797 as a class I drug with a profile more similar to that of the Ic agent propafenone than that of Ia or Ib drugs (Winslow et al, 1989), results which were confirmed in vivo using a known antifibrillatory dose (0.5 mg kg-') in dogs with 5 to 6 day-old myocardial infarcts . However, the consistent and potent antifibrillatory actions of Org 7797 observed in rat, canine and porcine models of myocardial ischaemia (Janse et al, 1990;Winslow et al, 1991) are difficult to reconcile with a Ic sodium channel blocking action since agents of this class, which, whilst having proven antiarrhythmic effects, do not appear to prevent, and indeed may exacerbate, ventricular fibrillation during ischaemia both in animals (e.g.…”

Section: Introductionmentioning

confidence: 80%

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

Leboeuf¹,

Basiez²,

Massingham³

1993

British J Pharmacology

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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.

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Section: Introductionmentioning

confidence: 80%

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

Leboeuf¹,

Basiez²,

Massingham³

1993

British J Pharmacology

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“…During the action potential (open and inactivated states) drug association to the channel occurs, while during diastole (resting state) drug dissociation and therefore relief from block is preferred. Class Ia and Ic drugs dissociate relatively slowly (comparing to physiological cycle lengths) from the sodium channels during diastole, [27][28][29][30][31][32][33][34][35][36][37][38][39] which action can be characterized by a recovery time constant longer than about 2 sc. The similar recovery of V max (or sodium channel time constant) for Ib drugs is considerably faster, 40-43 the recovery time constant is less than 500 to 1000 ms. As a consequence, class Ia and Ic drugs like quinidine, disopyramide, flecainide, encainide, propafenone, etc.…”

Section: Sodium Currentmentioning

confidence: 99%

Antiarrhythmic agents: Current status and perspectives

Mátyus¹,

Varró²,

Papp³

et al. 1997

Med. Res. Rev.

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“…This compound has been shown to be effective against aconitineinduced and ischaemia-induced arrhythmias in rodents and to inhibit the fast inward sodium current in guinea-pig atria (Campbell et al, 1986). Org 7797 has been further subclassified as a Ic agent on the basis of the kinetics of onset of rate-dependent sodium channel block in porcine isolated cardiac tissue (Winslow et al, 1989a) and on its electrophysiological actions in vivo (Campbell et al, 1991). The aim of the present study was to explore the antiarrhythmic potential of this compound against ischaemia-related arrhythmias in more detail and to compare its activity with that of two other Ic agents, flecainide and propafenone.…”

Section: Introductionmentioning

confidence: 99%

Effects of Org 7797 on early, late and inducible arrythmias following coronary artery occlusion in rats and dogs

Winslow¹,

Campbell²,

Barron³

et al. 1991

British J Pharmacology

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1 The class Ic steroidal antiarrhythmic agent, Org 7797, was compared with two other Ic agents, flecainide and propafenone for intravenous activity against ischaemia-related cardiac arrhythmias and for electrophysiological actions in vivo. In addition the haemodynamic effects of Org 7797 were assessed in greyhounds. 2 Org 7797 (0.5mgkg-1) significantly reduced the expected incidence of early ischaemia-induced ventricular fibrillation (VF) in rats and greyhound dogs and at doses of 0.5-1.0mgkg-1 antagonized reperfusion-induced arrhythmias. Comparative studies in rats showed Org 7797 to be 2-4 times more potent than flecainide or propafenone. 3 Org 7797 (0.5mg kg-1) slowed intracardiac conduction in anaesthetized beagles and again was at least 2-4 times more potent than flecainide or propafenone.4 Org 7797 (0.5 and 2.0mgkg-'), flecainide (1.0 and 2.0mgkg 1) or propafenone (0.5 and 2.0mgkg 1), did not significantly prevent induction of tachyarrhythmias (VT) in dogs with 5-6 day old myocardial infarcts although all 3 drugs appeared to prevent induced VF. All 3 drugs (notably fecainide) did however reduce the VT rate.5 All 3 drugs (1-2 mg kg 1) suppressed spontaneous tachyarrhythmias in conscious beagle dogs with 1-2 day old infarcts. Propafenone was the least effective.6 In an antifibrillatory dose (0.5mgkg-'), the major haemodynamic effect of Org 7797 was a 10% increase in peripheral vascular resistance. Stroke volume, cardiac output and coronary blood flow were unchanged. In therapeutic doses, Org 7797 was also less negatively chronotropic than flecainide. 7 It was concluded that Org 7797 is a potent antifibrillatory agent which is haemodynamically well tolerated. Higher doses are required to suppress late ischaemia-induced tachyarrhythmias which suggest that its antifibrillatory effects are the consequence of an action other than, or in addition to, sodium channel block.

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Electrophysiologic Effects of Org 7797, a New Steroidal Antiarrhythmic Agent

Cited by 11 publications

References 0 publications

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

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

Antiarrhythmic agents: Current status and perspectives

Effects of Org 7797 on early, late and inducible arrythmias following coronary artery occlusion in rats and dogs

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