P106Computational modeling of the cellular mechanisms of cardiac pacemaking

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The cellular basis of heart's pacemaking, and specifically the degree of contribution of the different mechanisms involved, is still debated. Reliable computational models of the sinoatrial (SAN) action potential (AP) may help gain a deeper understandingof the phenomenon. Recently, novel models incorporating a detailed calcium-handling dynamics have been proposed, but they fail in reproducing experimental effects of "funny" current (If) reduction. We therefore developed a SAN AP model, based on available experimental data, to reproduce and investigate autonomic and drug-induced rate modulation.

Cellcompartmentalization and all the intracellular Ca2+ handling mechanisms were formulated as in the Maltsev-Lakatta model. Membrane current equations were revised on the basis of published experimental data. Autonomic modulation and drug effects (Acetylcholine, Isoprenaline, Ivabradine, Cesium, BAPTA, Ryanodine, CPA) were simulated by modifying the affected currents.

The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges:176ms AP duration, 329ms cycle length, 73mV AP amplitude, -56mV maximum diastolicpotential and 6.23V/s maximum upstroke velocity. More importantly, the model reproduces the autonomic and drug-induced rate modulationntal findings. In particular, 18% Cesium-induced (5mM) and and 20% Ivabradine-induced (3μM) rate reductions were reproduced. Model testing of Ryanodine, CPA and BAPTA effects showed slowing of rate without cessation of beating. Our up-to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca-related system by specific drugs, making it a useful tool for further investigations. Simulation results suggest that a detailed description of the intracellular calcium fluxes is fully compatible with the observation that If is a major component of pacemaking and rate modulation.

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