%0 Journal Article %1 Hund_2004_3168 %A Hund, Thomas J %A Rudy, Yoram %D 2004 %J Circulation %K 15505083 4-Aminopyridine, Action Animals, Artificial, Biology, Calcium Calcium, Cardiac Cardiac, Cardiovascular, Channel, Channels, Chlorides, Computational Computer Conduction Dependent Dogs, Exchanger, Extramural, Gov't, Heart Ion Isoenzymes, Kinase, L-, Models, Myocytes, N.I.H., Non-U.S. P.H.S., Pacing, Pericardium, Potassium Potassium, Potentials, Protein Rate, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Simulation, Sodium Sodium, Sodium-Calcium Support, Symporters, System, Transport, Type, U.S. Ventricles, Voltage-Gated, {C}a$^{2+}$-Calmodulin %N 20 %P 3168--3174 %R 10.1161/01.CIR.0000147231.69595.D3 %T Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model. %U http://dx.doi.org/10.1161/01.CIR.0000147231.69595.D3 %V 110 %X 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 Ca$^2+$ transient (CaT) and action potential duration (APD) rate dependence. METHODS AND RESULTS: The Ca$^2+$/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca$^2+$-release formulation, Ca$^2+$ 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.

@article{Hund_2004_3168, abstract = {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 {C}a$^{2+}$ transient (CaT) and action potential duration ({APD}) rate dependence. METHODS {AND} RESULTS: The {C}a$^{2+}$/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel {C}a$^{2+}$-release formulation, {C}a$^{2+}$ 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Hund, Thomas J and Rudy, Yoram}, biburl = {https://www.bibsonomy.org/bibtex/271db1cde17e4600867cef7b786003cec/hake}, comment = {Supplement in Hund_2004_3168_supl.pdf}, description = {The whole bibliography file I use.}, doi = {10.1161/01.CIR.0000147231.69595.D3}, file = {Hund_2004_3168.pdf:Hund_2004_3168.pdf:PDF}, interhash = {2d8c0feb9fa6e321232a1e610370acaa}, intrahash = {71db1cde17e4600867cef7b786003cec}, journal = {Circulation}, key = 113, keywords = {15505083 4-Aminopyridine, Action Animals, Artificial, Biology, Calcium Calcium, Cardiac Cardiac, Cardiovascular, Channel, Channels, Chlorides, Computational Computer Conduction Dependent Dogs, Exchanger, Extramural, Gov't, Heart Ion Isoenzymes, Kinase, L-, Models, Myocytes, N.I.H., Non-U.S. P.H.S., Pacing, Pericardium, Potassium Potassium, Potentials, Protein Rate, Receptor Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Simulation, Sodium Sodium, Sodium-Calcium Support, Symporters, System, Transport, Type, U.S. Ventricles, Voltage-Gated, {C}a$^{2+}$-Calmodulin}, month = Nov, number = 20, pages = {3168--3174}, pii = {95.D3}, pmid = {15505083}, timestamp = {2009-06-03T11:21:15.000+0200}, title = {Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model.}, url = {http://dx.doi.org/10.1161/01.CIR.0000147231.69595.D3}, volume = 110, year = 2004 }