title: A proarrhythmic response to sodium channel blockade: modulation of the vulnerable period in guinea pig ventricular myocardium.
abstract: 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.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York.
authors.forename: V V
authors.initials: VV
authors.lastname: Nesterenko
authors.forename: A A
authors.initials: AA
authors.lastname: Lastra
authors.forename: L V
authors.initials: LV
authors.lastname: Rosenshtraukh
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D005424:Flecainide / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D016293:Moricizine / Q000008:administration & dosage / Q000494:pharmacology*; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015222:Sodium Channels; D016293:Moricizine; D011802:Quinidine; D005424:Flecainide