A proarrhythmic response to sodium channel blockade: modulation of the vulnerable period in guinea pig ventricular myocardium

The vulnerable period (VP) is an interval of time during the cardiac cycle within which premature stimulation may lead to trains of responses (one: many stimulus-response coupling). Although the VP parallels the recovery of sodium channel availability, modulators of its boundaries remain unclear. Nu...

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Bibliographic Details
Published inJournal of cardiovascular pharmacology Vol. 19; no. 5; p. 810
Main Authors Nesterenko, V V, Lastra, A A, Rosenshtraukh, L V, Starmer, C F
Format Journal Article
LanguageEnglish
Published United States 01.05.1992
Subjects
Action Potentials - drug effects
Animals
Arrhythmias, Cardiac - physiopathology
Flecainide - administration & dosage
Flecainide - pharmacology
Guinea Pigs
Heart - drug effects
Heart - physiology
In Vitro Techniques
Moricizine - administration & dosage
Moricizine - pharmacology
Quinidine - administration & dosage
Quinidine - pharmacology
Sodium Channels - drug effects
Sodium Channels - metabolism
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Summary:The vulnerable period (VP) is an interval of time during the cardiac cycle within which premature stimulation may lead to trains of responses (one: many stimulus-response coupling). Although the VP parallels the recovery of sodium channel availability, modulators of its boundaries remain unclear. Numerical studies of a uniform cable demonstrated that reduction in sodium channel availability increased the range of premature stimuli, resulting in unidirectional block, a precursor of reentrant activation. Consequently, we hypothesized that the kinetics of use-dependent sodium channel blockade could reflect one dimension of a drug's proarrhythmic potential. In strips from guinea pig right ventricle, we probed the boundaries of the VP in the presence of use-dependent sodium channel antagonists utilizing a train of stimuli followed by a premature stimulus. Under drug-free conditions when the sites of drive and premature stimulation were the same, the VP was less than 4 ms in duration. When the drive and premature sites were different, the drug-free VP was greater than 5 ms in 22 of 24 preparations and 0 in the other two, with an average VP duration of 16 +/- 10 ms (mean +/- SD). In the presence of 1 microM moricizine, VP = 17 +/- 4 ms; 12 microM moricizine, VP = 35 +/- 4 ms; 3 microM flecainide, VP = 50 +/- 17 ms; and 4 microM quinidine, VP = 2 +/- 1 ms. These results suggest that residual unsuppressed premature ventricular contractions (PVCs) in the presence of some class 1 drugs have a greater potential for initiating a proarrhythmic response than PVCs in the absence of a class 1 drug.
ISSN:0160-2446