Computer modeling of current-induced early afterdepolarizations in
isolated guinea pig ventricular myocytes.
Nordin, Charles, and Zhen Ming.
Department of Medicine, Albert Einstein College of Medicine, Bronx,
New York
APStracts 2:0081H, 1995.
We tested the ability of a computer model of transmembrane current and
intracellular Ca2- flux in the isolated guinea pig myocyte (28) to
reproduce data from prior experimental studies and new data presented
in this paper regarding the behavior of early afterdepolarizations
induced by constant inward current, a response closely related to the
effect of localized injury currents in damaged myocardial syncytia.
The goals of the study were to confirm the model's capacity to
reproduce relevant experimental responses for which it was not
originally designed, and to analyze the mechanisms underlying the
experimental phenomena. Under normal conditions, current-induced
early afterdepolarizations in the model developed only from membrane
potentials associated with L-type Ca2- channel window current, and
the magnitude of upstrokes was unaffected by blockade of either
delayed rectifier K- current or sarcoplasmic reticulum Ca2- release.
Following Ca2- loading secondary to either reduced extracellular [K-]
or inhibition of Na-K ATPase activity, the threshold potential for
current-induced early afterdepolarizations in the model, as with
experimental myocytes, shifted to membrane potentials negative to the
threshold potential for Ca2- channel activation, and upstrokes were
initiated by inward currents generated by electrogenic Na-Ca exchange
following oscillatory Ca2- release from the sarcoplasmic reticulum.
New experiments presented in this paper demonstrate that bursts of
rapid depolarizing stimulations terminate current-induced early
afterdepolarizations. Termination is caused by transient
hyperpolarizations which increase as a function of number or duration
of stimulations, and if strong enough cross the all-or-none threshold
and lead to full repolarization. This experimental response was
accurately simulated by the model through interactions that led to
activation of delayed rectifier current, inactivation of Ca2- channel
current, and a reduction in inward Na-Ca exchange current secondary
to altered intracellular Ca2- cycling. Our results confirm that the
model accurately simulates a wide range of responses beyond its
original experimental constraints and suggest that current-induced
early afterdepolarizations are initiated and terminated by complex
processes that vary with specific experimental conditions and involve
multiple currents.
Received 23 August 1994; accepted in final form 4 January 1995.
APS Manuscript Number H763-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 21 March 1995.