Computer model of current-induced early afterdepolarizations in guinea pig ventricular myocytes.
We tested the ability of a computer model of transmembrane current and intracellular Ca2+ flux in the isolated guinea pig myocyte (Nordin, C., Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H2117-H2136, 1993) to reproduce data from prior experimental studies and new data presented in this study 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. After Ca2+ loading secondary to either reduced extracellular [K+] or inhibition of Na(+)-K(+)-adenosinetriphosphatase 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. 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 study 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. We 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.
Nordin
C
C
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ming
Z
Z
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003198:Computer Simulation; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D011802:Quinidine / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013997:Time Factors
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012433:Ryanodine; D012964:Sodium; D011802:Quinidine; D011188:Potassium; D002118:Calcium