AJP - Heart and Circulatory Physiology, Vol 270, Issue 2 447-H465, Copyright © 1996 by American Physiological Society

ARTICLES

Response of Ca(2+)-loaded, depolarized guinea pig myocytes to critically timed premature stimulations

C. Nordin
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Single premature stimulations during trains of nondriven action potentials induced by depolarization normally cause a transient hyperpolarization of diastolic membrane potential before the subsequent spontaneous upstroke. However, rare, marked transient depolarizations have also been reported. This paper presents experimental data and computer simulations that characterize transient depolarization following premature stimulations and investigate the role of intracellular [Ca2+] in generating this unusual response. In isolated guinea pig myocytes, transient depolarizations (range 4-58 mV) consistently occurred following stimulations 100-160 ms after the upstroke of spontaneous action potentials during exposure to K(+)-free Tyrode solution, which raises intracellular [Ca2+]. In contrast, no transient depolarizations developed when stimulations were delivered during injection of constant inward current or brief exposure to very low dose of Ba2+ (250-500 microM). The experimental response to K(+)-free Tyrode solution was reproduced by a computer model of the transmembrane current and intracellular Ca2+ flux of an isolated guinea pig ventricular myocyte (24) following reduction of extracellular [K+] below 1 mM. Transient depolarization was generated primarily by Na/Ca exchange. Simulations using only those equations governing intracellular Ca2+ cycling revealed that bursts of Ca2+ into the myoplasm after Ca2+ loading caused a transient increase in trough myoplasmic [Ca2+] when the coupling interval following the upstroke of a myoplasmic [Ca2+] oscillation was nearly identical to those coupling intervals that caused pacing-induced transient depolarization of membrane potential after the upstroke of an action potential. These results suggest that transient depolarizations following nondriven action potentials arise from critically timed, stimulus-induced perturbation of intracellular [Ca2+] oscillations associated with Ca2+ overload. Simulations using a multicellular model suggest that critically timed premature stimulations can initiate trains of depolarized, nondriven action potentials in otherwise quiescent, Ca(2+)-overloaded heterogeneous syncytia by a similar mechanism.