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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 Vs(-1) maximum upstroke velocity. Rate modulation by I(f) -blocking drugs agrees with experimental findings: 20% and 22% caesium-induced (5mM) 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+)-related system by BAPTA, making it a useful tool for further investigation. 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 rate modulation. |
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