An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation

Abstract

Key points• Computational models of the electrical activity of sinoatrial cells (SANCs) have been proposed to gain a deeper understanding of the cellular basis of cardiac pacemaking.• However, they fail to reproduce a number of experimental data, among which are effects measured after modifications of the 'funny' (I f ) current.• We developed a novel SANC mathematical model by updating the description of membrane currents and intracellular mechanisms on the basis of experimental acquisitions, in an attempt to reproduce pacemaker activity and its physiological and pharmacological modulation.• Our model describes satisfactorily experimental data on pacemaking regulation due to neural modulation, I f block and inhibition of the intracellular Ca 2+ handling.• Computer simulation results suggest that a detailed description of the intracellular Ca 2+ fluxes is fully compatible with the observation that I f is a major component of pacemaking and heart rate modulation.Abstract The cellular basis of cardiac pacemaking is still debated. Reliable computational models of the sinoatrial node (SAN) action potential (AP) may help gain a deeper understanding of the phenomenon. Recently, novel models incorporating detailed Ca 2+ -handling dynamics have been proposed, but they fail to reproduce a number of experimental data, and more specifically effects of 'funny' (I f ) current modifications. We therefore developed a SAN AP model, based on available experimental data, in an attempt to reproduce physiological and pharmacological heart rate modulation. Cell compartmentalization and intracellular Ca 2+ -handling mechanisms were formulated as in the Maltsev-Lakatta model, focusing on Ca 2+ -cycling processes. Membrane current equations were revised on the basis of published experimental data. Modifications of the formulation of currents/pumps/exchangers to simulate I f blockers, autonomic modulators and Ca 2+ -dependent mechanisms (ivabradine, caesium, acetylcholine, isoprenaline, BAPTA) were derived from experimental data. The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges: 352 ms cycle length, 80 mV AP amplitude, −58 mV maximum diastolic potential (MDP), 108 ms APD 50 , and 7.1 V s −1 maximum upstroke velocity. Rate modulation by I f -blocking drugs agrees with experimental findings: 20% and 22% caesium-induced (5 mM) and ivabradine-induced (3 μM) rate reductions, respectively, due to changes in diastolic depolarization (DD) slope, with no changes in either MDP or take-off potential (TOP). The model consistently reproduces the effects of autonomic modulation: 20% rate decrease with 10 nM acetylcholine and 28% increase with 1 μM isoprenaline, again entirely due to increase in the DD slope, with no changes in either MDP or TOP. Model testing of BAPTA effects showed slowing of rate, −26%, without cessation of beating. Our up-to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca 2+ -rela...

In Quest of a Sinoatrial Cell Model to Assess the Functional Effects of Mutations in the HCN4 Funny Current Gene

“…The source code of the Maltsev-Lakatta and SeveriDiFrancesco models [15,16] was taken from the model repository on the CellML website [17]. For consistency and to prevent slow drifts, we set the intracellular Na + concentration of the Severi-DiFrancesco model [16] to a constant value, as in the Maltsev-Lakatta model [15].…”

“…For consistency and to prevent slow drifts, we set the intracellular Na + concentration of the Severi-DiFrancesco model [16] to a constant value, as in the Maltsev-Lakatta model [15].…”

“…These are the models by Maltsev and Lakatta [15] ('Maltsev-Lakatta model') and Severi et al [16] ('Severi-DiFrancesco model'). Both models represent the electrophysiological behavior of a single isolated 32-pF rabbit SAN cell and are based on the large amount of experimental data that have become available over the years, largely obtained in patch-clamp experiments on isolated rabbit SAN cells.…”

Recent progress in multi-scale models of the human atria

“…Animal models of the SAN and atrio-ventricular node (AVN, the secondary cardiac pacemaker) now contain detailed ionic formulations and sophisticated intracellular calcium handling systems, and as such model both the membrane and calcium clocks [36,37] (for a discussion on the roles of these different clocks the reader is referred to [38]). Electrophysiological data on the pacemaker regions of human and large mammal species are very limited.…”

High Heart Rate in Pregnancy Is Modulated by Augmented Expression of an Ion Channel, HCN-2, in Pacemaker Tissue

“…7 In situations when an important physiological response is generated by a net current change that is very small (in fact, in this case, it is near the resolution of the whole-cell patch-clamp method), it is useful to integrate and illustrate the experimental findings through the use of a mathematical model. This approach has been used to advantage in previous studies of cardiac pacemaker mechanisms in the rabbit 8 and mouse, 9 and these models continue to be improved as new experimental data sets are published. We have adapted the original Bondarenko et al 10 model of the mouse ventricular action potential to simulate the action potential and pacemaker depolarization in mouse sinoatrial node myocyte.…”