Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model.
BACKGROUND
Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca2+ transient (CaT) and action potential duration (APD) rate dependence.


RESULTS
The Ca2+/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca2+-release formulation, Ca2+ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I(Ca(L)) reduction, with additional contributions from I(to1), I(NaK), and late I(Na). CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate-dependent property depended on CaMKII activity.


CONCLUSIONS
CaMKII is an important determinant of the rate dependence of CaT but not of APD, which depends on ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for modeling effects of other regulatory pathways on cell function.
Hund
Thomas J
TJ
Department of Biomedical Engineering, Washington University, St. Louis, MO 63130-4899, USA.
Rudy
Yoram
Y
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D002712:Chlorides / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels; D004285:Dogs; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D017136:Ion Transport; D007527:Isoenzymes / Q000502:physiology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D010496:Pericardium / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D049992:Sodium Chloride Symporters; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D027981:Symporters / Q000378:metabolism
D020746:Calcium Channels, L-Type; D002712:Chlorides; D051668:Delayed Rectifier Potassium Channels; D007527:Isoenzymes; D024642:Potassium Channels, Voltage-Gated; D019837:Ryanodine Receptor Calcium Release Channel; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D019831:Sodium-Calcium Exchanger; D027981:Symporters; D012964:Sodium; D015761:4-Aminopyridine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011188:Potassium; D002118:Calcium