title: Modification of the frequency- and voltage-dependent effects of quinidine when administered in combination with tocainide in canine Purkinje fibers.
abstract: Frequency- and voltage-dependent modification of drug-induced inhibition of maximal upstroke velocity of the action potential (Vmax) by the combined administration of two class I antiarrhythmic drugs was studied in canine Purkinje fibers, taking depression of upstroke velocity as an indicator of sodium channel blockade. The kinetics of onset of drug-induced Vmax depression and the time course of Vmax recovery were studied after exposure to therapeutic concentrations of tocainide (50 microM) and quinidine (5 microM) both singly and in combination. The rate constant for onset of block during a drive train at a cycle length of 600 msec was 0.95 +/- 0.32 pulses in the presence of tocainide and 5.61 +/- 0.50 pulses in the presence of quinidine. The magnitude of block was three times greater with quinidine than with tocainide. The magnitude of block produced by the combination was no greater than that produced by quinidine alone and may be partly due to abbreviation of action potential duration by tocainide. Onset of block in the presence of the combination was best fitted by a double exponential with rate constants of 0.88 +/- 0.19 and 6.47 +/- 1.36 pulses. Vmax recovery after termination of a rapid train of impulses was delayed by both drugs. Poststimulation recovery from either tocainide- or quinidine-induced block was characterized by a single time constant (1.04 +/- 0.49 and 4.81 +/- 0.76 sec, respectively), while that of the combination was characterized by two time constants (0.43 +/- 0.22 and 5.94 +/- 0.56 sec), presumably corresponding to dissociation of each drug from the sodium channel receptor. The mixture of the two drugs produced a large depression of Vmax of early diastolic premature responses without producing much further depression of Vmax than that produced by quinidine alone at longer coupling intervals. The time constant of recovery from tocainide-induced block was greatly dependent upon membrane potential. After steady-state changes in frequency, the combination produced a greater depression of Vmax at rapid heart rates compared with that produced by quinidine alone, but abbreviated action potential duration more at slower heart rates. Addition of tocainide to fibers equilibrated with quinidine shifted the Vmax-membrane potential relationship to more hyperpolarized potentials, resulting in greater depression of Vmax at more depolarized membrane potentials with little or no additional depression of Vmax at more negative membrane potentials. The results provide a rationale for a possible enhanced antiarrhythmic efficacy of a combination of two class I drugs that have different kinetics of interaction with the sodium channel.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004285:Dogs; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011802:Quinidine / Q000008:administration & dosage* / Q000494:pharmacology; D016677:Tocainide
chemical_list: D007473:Ion Channels; D016677:Tocainide; D008012:Lidocaine; D011802:Quinidine