Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length.

Abstract

SUMMARY. Marked QT prolongation with induction of polymorphous ventricular tachycardia ('Torsades de Pointes') is a well-described phenomenon during quinidine therapy, frequently occurring at low plasma quinidine concentrations, low serum potassium, and slow heart rates. We have therefore assessed the dose-electrophysiological effects of quinidine as a function of extracellular potassium and cycle length in canine Purkinje fibers, using standard microelectrode techniques. Quinidine (1 MM) prolonged action potential at 90% repolarization, while leaving phase zero upstroke slope (Vm«) unchanged at a cycle length 300-8000 msec; at 10 MM, V,,,,,, depression became evident. Increases in the action potential at 90% repolarization were most marked at long cycle lengths and low extracellular potassium (in contrast to V^ depression) and were partially reversed by tetrodotoxin (1 M M )-The relationship between log of cycle length and action potential at 90% repolarization was linear (for cycle length 300-8000 msec) in the absence of quinidine. Quinidine increased the slope of this relationship in a concentration-related fashion, whereas increasing extracellular potassium shifted the curve rightward (without changing slope), regardless of the presence or absence of quinidine. Action potentials were also measured following pauses of 5-60 seconds. In the absence of quinidine, the action potential depolarization returned to its baseline value in a monoexponential fashion (time constant 36.0 ± 4.9 sec, mean ± SE, n = 10). In the presence of 1 JIM quinidine, this return was better fit as a biexponential process (time constants 4.2 ± 1 . 2 and 40.7 ± 6.2 seconds, n = 14). At slow stimulation rates (cycle length greater than 4000 msec) in low extracellular potassium (2.7 mM), quinidine produced early afterdepolarizations in 7/14 (50%) of fibers at 1 MM and 14/18 (78%) at 10 MM. Early afterdepolarizations were eliminated by increasing stimulation rates, raising the extracellular potassium concentration to 5 mM, or adding tetrodotoxin. These data suggest that prolongation by quinidine of action potentials at 90% repolarization is multifactorial, with both a 'tonic' prolonging effect and a prominent frequency-dependent action potential shortening effect. At long cycle lengths and low extracellular potassium, low quinidine concentrations consistently produced early afterdepolarizations. The parallels between this form of triggered activity and clinical arrhythmias induced by quinidine suggest that early afterdepolarizations may play a role in quinidine-induced Torsades de Pointes. (Circ Res 56: 857-867, 1985)

Depression of maximum rate of depolarization of guinea‐pig ventricular action potentials by metabolites of encainide

“…Recent evidence has implicated early afterdepolarizations (such as those observed with ODE and MODE in the present study) in the pathogenesis of some of these 'proarrhythmic' effects, particularly in the genesis of a bizarre form of ventricular tachycardia characteristic of drug-induced arrhythmias, known as 'torsade de pointes' (Roden & Hoffman, 1985). It is interesting in this context to note that the incidence of proarrhythmic effects in a number of studies of this phenomenon, has been higher for patients on encainide than for any other agent (Winkle et al, 1981;DiBianco et al, 1982;Podrid, 1985;Morganroth et al, 1986;Zipes, 1988).…”

Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Effects of stimulation rate, potassium, and magnesium.

“…Quinidine 2 but not phase 3 EADs and increase the manifestation of both phase 2 and phase 3 triggered activity (unpublished observation from this laboratory). Like calcium channel blockers, magnesium greatly diminishes the amplitude of phase 2, but not phase 3, EADs but suppresses both types of triggered activity in quinidine-treated fibers.…”

“…6 Although the mechanisms underlying torsade de pointes are not well defined, EAD-induced triggered responses may be the initiating events.' 2,7,8 Recent in vivo studies have provided evidence for EAD and triggered activity as the underlying mechanism of polymorphic ventricular tachyarrhythmias in dogs exposed to cesium chloride9'10 or anthopleurin.1" Recent clinical and experimental studies also report the successful suppression of drug-induced torsade de pointes after intravenous magnesium sulfate administration. 10"12 In this study, we use standard microelectrode techniques to evaluate the effects of stimulation frequency and extracellular potassium and magnesium concentration on action potential duration, EAD, and triggered activity in canine Purkinje fibers exposed to therapeutic concentrations of quinidine for a period of 90 minutes or more.…”

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

“…In the case of quinidine, excessive prolongation of the APD and induction of EADs are seen at low concentrations of the drug and at slow heart rates and is thought to be explained by the reverse frequency dependence of the compound leading to an increased block of IK r and decreased block of INa at low frequencies (Roden et al, 1985). Reverse frequency dependence is absent or very small in the case of AZD7009.…”