Abstract
We have developed a mathematical model of the rabbit atrial myocyte as a tool to examine the ionic bases underlying rate-dependent changes in action potential waveshape. Such changes have been postulated to result primarily from two causes: (1) incomplete reactivation of ionic currents and (2) rate-dependent changes in ion concentration gradients. The model has incorporated biophysical data to quantify the specific ultrastructural morphology, ion buffering, and sarcolemmal electrophysiology of the rabbit atrial cell. In particular, mathematical forms describing ionic currents identified in rabbit atrium are based on whole-cell voltage-clamp data from enzymatically isolated rabbit cardiomyocytes. We address the rate-dependent effects of incomplete reactivation by accounting for the reactivation timecourse of the largest ionic currents (fast sodium, transient outward, and long-lasting calcium currents) found in rabbit atrium. Modeling simulations are obtained by numerical integration of the relatively stiff system of 28 coupled ordinary differential equations. Our model can simulate (1) the whole-cell voltage-clamp data upon which it is based, (2) the nominal action potential waveshape at a typical, physiological rate of stimulation, and (3) changes in waveshape that occur as the stimulus rate is varied. As changes in early repolarization have been correlated experimentally with alterations in the transient outward current (It), the model offers a semi-quantitative interpretation of the importance of It to rate-dependent waveshape changes. Our model also predicts the intracellular [Ca2+]i-transient that occurs during the action potential. We have utilized our model to examine action potential refractoriness by simulating (1) the reponse elicited by stimulation of a “premature” action potential and (2) the predicted waveshape changes that occur at high rates of cell stimulation. These responses provide insight into the electrophysiological changes that may accompany atrial arrhythmia.
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