Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence.
A model of the cardiac ventricular action potential that accounts for dynamic changes in ionic concentrations was used to study the mechanism, characteristics, and rate dependence of early after depolarizations (EADs). A simulation approach to the study of the effects of pharmacological agents on cellular processes was introduced. The simulation results are qualitatively consistent with experimental observations and help resolve contradictory conclusions in the literature regarding the mechanism of EADs. Our results demonstrate that: 1) the L-type calcium current, ICa, is necessary as a depolarizing charge carrier during an EAD; 2) recovery and reactivation of ICa is the mechanism of EAD formation, independent of the intervention used to induce the EADs (cesium, Bay K 8644, or isoproterenol were used in our simulations, following similar published experimental protocols); 3) high [Ca2+]i is not required for EADs to develop and calcium release by the sarcoplasmic reticulum does not occur during the EAD; 4) although the primary mechanism of EAD formation is recovery of ICa, other plateau currents can modulate EAD formation by affecting the balance of currents during a conditional phase before the EAD take-off; and 5) EADs are present at drive cycle lengths longer than 1000 ms. Because of the very long activation time constant of the delayed rectifier potassium current, IK, the activation gate of IK does not deactivate completely between consecutive stimuli at fast rates (drive cycle length < 1000 ms). As a result, IK plays a key role in determining the rate dependence of EADs.
Zeng
J
J
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.
Rudy
Y
Y
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D055592:Biophysical Phenomena; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002586:Cesium / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017136:Ion Transport; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008955:Models, Cardiovascular; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D016276:Ventricular Function
D015220:Calcium Channels; D015221:Potassium Channels; D002586:Cesium; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D012964:Sodium; D007545:Isoproterenol; D002118:Calcium