Published Online
on October 25, 2004

A more recent version of this article appeared on November 16, 2004

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Submitted on January 29, 2004
Revised on April 19, 2004
Accepted on June 7, 2004

Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

Thomas J. Hund PhD and Yoram Rudy PhD^*

From the Departments of Biomedical Engineering (T.J.H., Y.R.) and Pathology (T.J.H.), Washington University, St. Louis, Mo.

^* To whom correspondence should be addressed. E-mail: rudy{at}wustl.edu.

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.

Methods and 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.

Key words: electrophysiology • action potentials • calcium • ion channels

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