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

Abstract

Early afterdepolarization (EAD)-induced triggered activity is thought to contribute to the cardiac arrhythmogenic effects of several class I antiarrhythmic agents. The combination of quinidine therapy, bradycardia, and hypokalemia is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia commonly associated with long QT intervals. Recent clinical reports have shown suppression of quinidine-induced torsade de pointes with intravenous administration of magnesium sulfate. To provide further understanding of these relations, we used standard microelectrode techniques to examine the time course of quinidineinduced action potential prolongation, EAD, and triggered activity development and the dependence of these changes on [K+]0, [Mg2+]O, and stimulation frequency in isolated Purkinje fiber preparations exposed to low concentrations of the drug. At slow stimulation rates, the quinidineinduced increase of action potential duration was slow to develop and failed to reach a steady state after 3 hours of exposure to the drug. EAD and EAD-induced triggered activity generally became apparent 70-90 minutes after adding the drug. Quinidine produced triggered activity in 10 of 22 preparations superfused with Tyrode's solution containing normal [K+]0 (3.5-4.0 mM) and in six other preparations when [K%]0 was reduced. In the presence of normal [K]0, two types of EAD and triggered activity were distinguished. In four of 10 preparations, this activity arose from phase 2 of the action potential; in eight of 10, it was associated with phase 3; and in two experiments, both types were present in the same preparation. The incidence of both forms of triggered responses depended greatly on the rate of stimulation. Triggered activity arising from phase 3 was always manifest at rates considerably slower than those giving rise to phase 2 activity. Both forms of triggered activity were sensitive to changes in the extracellular concentration of potassium and magnesium. Lower-than-normal levels of these electrolytes facilitated the manifestation of triggered activity, whereas elevated levels suppressed or caused a shift in the frequency-dependence of the activity. In the clinic, the combination of bradycardia, hypokalemia, and quinidine is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia characterized in the electrocardiogram by "twisting" of the ventricular complexes around the isoelectric line. Torsade de pointes is commonly associated with QT

Possible pharmacological actions of magnesium in acute myocardial infarction.

“…Infusion of magnesium significantly reduced the amplitude of afterdepolarisations and the proportion of animals developing sustained ventricular arrhythmias in response to caesium chloride (Bailie et al, 1988). Another model for the long QT syndrome utilised the effect of quinidine (a class 1 antiarrhythmic) on canine Purkinje fibres in vitro (Davidenko et al, 1989 Of particular relevance to the present review is the effectiveness of magnesium in preventing arrhythmias arising in acutely ischaemic myocardium. There is empirical evidence for this both from randomized clinical trials in patients with acute myocardial infarction (Abraham et al, 1987;Ceremuzynski et al, 1989;Rasmussen et al, 1987;Schechter et al, 1990;Smith et al, 1986) and from experimental models of myocardial ischaemia (Barros et al, 1988;Crampton & Clark, 1983;Haverkamp et al, 1988).…”

Препараты Метаболического Действия В Комплексной Терапии Цереброкардиального Синдрома При Ишемическом Инсульте

“…Триггерная активность может быть обусловлена замедлением про-цесса реполяризации и удлинением потенциала действия [189], то есть может быть связана с удлинением интервала QT, а также с воздействи-ем катехоламинов [218].…”

Atrio-Ventricular Block-Induced Torsades de Pointes: An Update

“…These differences in action potential duration across the ventricular wall determine the transmural dispersion of repolarisation. When this transmural dispersion is exaggerated, opposite voltage gradients may occur and trigger oscillatory potentials, namely phase 2 early afterdepolarisations and sustained abnormal electrical activity (Dangman, 1981, Brachmann, 1983, Levine, 1985, Roden, 1985, Davidenko, 1989. Rarely, a single severe abnormality in a major repolarizing current can elicit an abnormal phenotype, as in congenital long QT syndrome (Roden, 1996).…”