Voltage‐ and Time‐dependent Depression of Maximum Rate of Depolarization of Guinea‐pig Ventricular Action Potentials by Two Steroidal Antiarrhythmic Drugs, Cci 22277 and Org 6001

Abstract

1 The voltage-and time-dependence of the depression of the maximum rate of depolarization ( V,,) by two steroidal anti-arrhythmic drugs, CCI 22277 and Org 6001 were studied in guinea-pig ventricle.2 At normal resting potentials CCI 22277 (2 Mm and 4lMm) produced very little depression of V,., at very low driving rates (resting block) but trains of stimuli at interstimulus intervals (ISI) of less than 10,000 ms led to an exponential decline in V,,= to a new plateau over 100-200 beats.

Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

“…The rate at which Vmax recovered towards the initial (resting block) level at the end of a train of stimuli was studied for seven drugs by adding a single extrastimuli at varying intervals after a series of trains of stimuli at a constant frequency (Campbell, 1982a). To reduce interference from the effects of extracellular K+ accumulation during rapid stimulation, the ISI of these conditioning trains was always >600 ms.…”

“…Rest periods were interposed between trains of stimuli to ensure full recovery from rate-dependent effects. The kinetics of this recovery were studied by applying single extra-stimuli at varying intervals after the end of a train, as previously described, (Campbell, 1982a).…”

“…The kinetics of this recovery were studied by applying single extra-stimuli at varying intervals after the end of a train, as previously described, (Campbell, 1982a Table 1 gives the values of molecular weight (of free base), pKa and log P (log of octanol: water partition coefficient at pH 7.4) for these 11 drugs and the sources of these data.…”

Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

“…Trains of stimuli were of sufficient duration to achieve a stable level of effect and rest periods (unstimulated) of at least 60 s were interposed between trains to allow full recovery from rate-dependent effects. The time course of this recovery process was studied by adding a single extrastimulus at varying intervals after a series of identical trains of stimuli at constant ISI (Campbell, 1982).…”

“…It is well-established that the ability of Class I antiarrhythmic agents to block the fast inward sodium channel and hence depress m of cardiac action potentials is enhanced at faster driving rates (Hondeghem & Katzung, 1980;Campbell, 1982;1983c;Courtney, 1980a). Several models of drug interaction with the sodium channel have been proposed to explain this behaviour (Hondeghem & Katzung, 1977;1980;1984;Courtney, 1980b,c;Grant et al, 1984).…”