Circulation, Vol 79, 674-686, Copyright © 1989 by American Heart Association
JM Davidenko, L Cohen, R Goodrow and C Antzelevitch
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
quinidine- induced action potential prolongation, EAD, and triggered
activity development and the dependence of these changes on [K+]0, [Mg2+]0,
and stimulation frequency in isolated Purkinje fiber preparations exposed
to low concentrations of the drug. At slow stimulation rates, the
quinidine-induced 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. Phase 2, but not phase 3, EADs were
abolished in response to increased [Mg2+]0. The data show a clear congruity
between the conditions that predispose to torsade de pointes in the clinic
and the conditions under which quinidine may induce triggered activity and
marked action potential prolongation in isolated Purkinje fibers.(ABSTRACT
TRUNCATED AT 400 WORDS)
ARTICLES
Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Effects of stimulation rate, potassium, and magnesium
Masonic Medical Research Laboratory, Utica, New York 13504.
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