Sensitivity of Rabbit Sino-atrial Node Cell Model to Some Ischemic Conditions

Christopher Oehmen, University of Tennessee, Memphis

Ischemia is defined as restriction or absence of oxygen supply to a region of tissue. Cardiac ischemia is characterized by several changes in regional and local chemistry. It is known that extracellular K+ concentration increases during ischemia and is associated with many negative effects on heart tissue, such as conduction velocity. In addition, intracellular Na+ concentration also increases during ischemia. In the absence of oxygen, intracellular pH and ATP concentration both decrease, also changing the properties of many ionic currents known to exist in the sino-atrial node. Since the sino-atrial node endogenously paces, it is responsible for the initiation of pacing in the heart, which leads to the contraction of the entire heart. This pacing activity can be modulated by environmental changes in cells, adversely affecting heart function. The purpose of this study was to apply sensitivity analyses to a computational model of a rabbit sino-atrial node cell to elucidate some of the effects of ischemia on the action potential of the cell. The model used in this study was modified from the rabbit sino-atrial node model of Demir et al. (1994), which was developed using experimental data available at the time of publication. The modified model contained additional K+ currents which were recently verified experimentally. The modified model was subject to sensitivity analyses concerning the ionic currents and ionic concentrations known to be affected during ischemia. Extracellular concentration of K+ and intracellular concentration of Na+ were simultaneously modulated, and the resulting action potential characteristics of the model were recorded. In addition, the effects of reducing various ionic current magnitudes on the action potential characteristics were also studied. It was found that intracellular Na+ concentration played a much more important role than K+ in determining some of the characteristics of the modeled action potential. The ionic currents having the most impact on action potential characteristics were shown to be the “L” type Ca2+ current (ICaL), the rapid delayed rectifier potassium current (IKr), the Na+/K+ pump (INaK), and the Na+/Ca2+ exchanger (INaCa). A model of ischemic action potentials was developed based on the results of the sensitivity analyses, and agrees with experimental observations concerning changes in peak overshoot and maximum diastolic potential during ischemia.

S. Demir, J. Clark, C. Murphey, and W. Giles, A mathematical model of a rabbit sinoatrial node cell American Journal of Physiology, vol. 266, pp. C832-C852, 1994.

Abstract Author(s): Christopher S. Oehmen, Semahat S. Demir