Frequency-dependent actions of phenytoin in adult and young canine Purkinje fibers.
Phenytoin has been reported to be particularly effective in the treatment of postoperative ventricular arrhythmias in children. The authors used standard microelectrode techniques to examine the developmental changes in the action of phenytoin on the transmembrane action potential of neonatal and adult canine Purkinje fibers. Their goals were to test whether developmental differences in phenytoin action on the action potential might explain the clinical observations and to evaluate the contribution of use-dependent reduction of Vmax and effects on slow responses to the antiarrhythmic action of phenytoin. In Tyrode's solution with [K+]0 = 4 mM, phenytoin at 5 and 10 micrograms/ml (concentrations comparable to therapeutic plasma levels) had no major effects on action potential characteristics or use dependence at either age. At [K+]0 = 6 mM, on decreasing the drive cycle length from 1300 to 300 msec, phenytoin reduced Vmax significantly and in a concentration-dependent manner. The magnitude of this action was similar at both ages. Conduction times were also significantly prolonged. The time constants for onset of (tau o) and recovery from (tau r) use-dependent block were similar in neonates and adults. The effects of phenytoin on slow responses were significant, although modest, at both ages, but there was no significant effect on conduction. This study indicates that in K+-depolarized Purkinje fibers, use-dependent reduction of the fast Na+ current is a major determinant of the antiarrhythmic action of phenytoin. In contrast to lidocaine and quinidine, no age-related changes in phenytoin action were found, underscoring the different developmental effects of individual antiarrhythmic drugs.
D000367:Age Factors; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D010672:Phenytoin / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D012995:Solubility
D000889:Anti-Arrhythmia Agents; D010672:Phenytoin; D008012:Lidocaine