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

摘要

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) 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 Ca²⁺-related system by BAPTA, making it a useful tool for further investigation. 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 rate modulation.