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

• Published in: The Journal of physiology 2012-09, Vol.590 (18), p.4483-4499
• Main Authors: Severi, Stefano, Fantini, Matteo, Charawi, Lara A., DiFrancesco, Dario
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Computational Physiology and Modelling; Computer Simulation; Heart Rate - physiology; Models, Cardiovascular; Rabbits; Sinoatrial Node - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2012.229435

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’ (If) 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, If block and inhibition of the intracellular Ca2+ handling. •  Computer simulation results suggest that a detailed description of the intracellular Ca2+ fluxes is fully compatible with the observation that If is a major component of pacemaking and heart rate modulation.   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 Ca2+‐handling dynamics have been proposed, but they fail to reproduce a number of experimental data, and more specifically effects of ‘funny’ (If) 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 Ca2+‐handling mechanisms were formulated as in the Maltsev–Lakatta model, focusing on Ca2+‐cycling processes. Membrane current equations were revised on the basis of published experimental data. Modifications of the formulation of currents/pumps/exchangers to simulate If blockers, autonomic modulators and Ca2+‐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 APD50, and 7.1 V s−1 maximum upstroke velocity. Rate modulation by If‐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) slo