Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium

Abstract

Decker KF, Heijman J, Silva JR, Hund TJ, Rudy Y. Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. Am J Physiol Heart Circ Physiol 296: H1017-H1026, 2009. First published January 23, 2009 doi:10.1152/ajpheart.01216.2008.-Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (Ito1), the slow component of the delayed rectifier K ϩ current (IKs), the L-type Ca 2ϩ channel current (ICa,L), and the Na ϩ -K ϩ pump current (INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca 2ϩ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca 2ϩ entry via ICa,L at fast rate drives increased Na ϩ -Ca 2ϩ exchanger Ca 2ϩ extrusion and Na ϩ entry, which in turn increases Na ϩ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets. arrhythmia; cardiac electrophysiology; mathematical modeling; ion channels CARDIAC ARRHYTHMIAS and sudden death involve complex myocardial activation patterns, including unidirectional block, reentry, and fibrillation. To understand the relations and transitions between these patterns, the ionic determinants of the response of healthy and diseased cardiac myocytes to complex patterns of excitation must be understood. The single-cell response to such excitation patterns depends on the complex interaction between ionic currents, intracellular ion concentrations, and membrane voltage. Computational cell models provide critical tools for exploring these interactions, allowing the development and testing of hypotheses about underlying ionic mechanisms based on careful integration of available experimental data (37). The dog is a common animal model for studying cell electrophysiology in a range of disease states. Our group and others have developed detailed mathematical models of the canine action ...

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

“…This has yielded novel insights on the importance of the Na/K pump in regulating cellular repolarization, both through direct effects caused by its electrogenic nature and indirectly through regulation of cell homeostasis. Importantly, these findings have been found to be consistent across species and cell types, including human, rabbit and dog and ventricular and atrial tissues [9,52,57,58,59,66]. Figures 4-6 describe some of the main results of these studies.…”

“…Figure 5A shows the characteristics of APD adaptation to sudden modifications in pacing rate in a model of human ventricular electrophysiology, under control conditions and partial block of the Na/K current [52]. Cellular electrophysiological models unveiled that the slow component of the APD adaptation process is predominantly dominated by intracellular Na + accumulation [9,52], and therefore Na/K inhibition significantly lengthens the adaptation time. The key role of the Na/K pump in modulating APD adaptation predicted by the simulations was confirmed experimentally using microelectrode action potential recordings in the presence of the Na/K blocker strophanthin, which at all doses significantly protracted the APD adaptation response, as illustrated in Figure 5B [52].…”

Intracellular Calcium Regulation in Canine Ventricular Myocytes: a Simulation Study

“…The action potential, underlying ionic currents and dynamic changes in ionic concentrations of an isolated canine ventricular myocyte were simulated using a modified version of the Decker-Rudy model [7,13], which includes a detailed formulation of calcium dynamics. A sensitivity analysis was performed by applying a one-at-atime variation in the ionic currents through the sarcolemma and the SR membrane.…”

“…In this study, we have used a well-known existing model of the action potential and ionic currents of a dog ventricular myocyte [7] to perform a sensitivity analysis to elucidate the ionic mechanisms that affect intracellular Ca 2+ regulation.…”

“…These computational studies rely on detailed and comprehensive mathematical models of action potentials for different animal species [6][7][8], including human [9]. Using this models, different studies have attempted to characterize the influence of the different sarcolemmal and SR ionic currents in AP and intracellular Ca 2+ preclinical biomarkers [10,11], but none of them has been carried out in dog, an animal that has widely been used in the past for drug and mutation effect studies [12,13].In this study, we have used a well-known existing model of the action potential and ionic currents of a dog ventricular myocyte [7] to perform a sensitivity analysis to elucidate the ionic mechanisms that affect intracellular Ca 2+ regulation. …”