Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers.
The recovery kinetics during diastole of various plateau currents are thought to control the restitution of action potential duration (APD). Based on the assumption that the recovery of the residual plateau Na current parallels that of Vmax, the hypothesis that Na current recovery kinetics influence the restitution of APD was tested. Drugs that reduced Vmax in a use-dependent manner (tetrodotoxin 3 microM, lidocaine 15 microM, mexiletine 20 microM) were compared with interventions that reduced Vmax in a simply tonic fashion [( Na]o 75 mM, [K]o 6.5 mM, disopyramide 30 microM). Microelectrode techniques and programmed stimulation were used to determine in vitro the kinetics of restitution of APD and of time-dependent recovery of Vmax during rest. Tetrodotoxin, lidocaine and mexiletine induced a blockade of Vmax that showed partial or full time-dependent unblocking in accordance with the known use dependence of their blocking action. Dissipation of the time-dependent component of the block in each case followed a single exponential time course, time constants being 163 +/- 12, 115 +/- 12 and 121 +/- 20 ms, respectively. Analysis of the kinetics of the APD restitution curves showed that the time constant of the fast decaying exponential component of restitution (T1) was prolonged by these drugs from 129 +/- 5 in control fibers to 295 +/- 17, 235 +/- 11 and 242 +/- 26 ms for tetrodotoxin, lidocaine and mexiletine, respectively (P less than .05). Low [Na]o and disopyramide reduced Vmax in a simply tonic fashion and did not significantly prolong the T1 component of APD restitution.(ABSTRACT TRUNCATED AT 250 WORDS)
Elharrar
V
V
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004206:Disopyramide / Q000494:pharmacology; D004285:Dogs; D004594:Electrophysiology; D006329:Heart Conduction System / Q000502:physiology*; D008012:Lidocaine / Q000494:pharmacology; D008801:Mexiletine / Q000494:pharmacology; D008839:Microelectrodes; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D008801:Mexiletine; D013779:Tetrodotoxin; D008012:Lidocaine; D012964:Sodium; D004206:Disopyramide