The cellular basis of cardiac pacemaking is still debated. Reliable computationalmodels 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 7.1Vs−1 maximum upstroke velocity. Rate modulation by If -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 decreasewith 10 nMacetylcholine and28%increasewith 1 μMisoprenaline, again entirely due C 2012 The Authors. The Journal of Physiology C 2012 The Physiological Society DOI: 10.1113/jphysiol.2012.229435 4484 S. Severi and others J Physiol 590.18 to increase in theDDslope,with no changes in eitherMDPorTOP.Model testing of BAPTAeffects 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 compatiblewith the observation that If is a major component of pacemaking and rate modulation.
An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation / S. Severi; M. Fantini; L. A. Charawi; D. DiFrancesco. - In: THE JOURNAL OF PHYSIOLOGY. - ISSN 0022-3751. - STAMPA. - 590:(2012), pp. 4483-4499. [10.1113/jphysiol.2012.229435]
An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation
SEVERI, STEFANO;
2012
Abstract
The cellular basis of cardiac pacemaking is still debated. Reliable computationalmodels 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 7.1Vs−1 maximum upstroke velocity. Rate modulation by If -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 decreasewith 10 nMacetylcholine and28%increasewith 1 μMisoprenaline, again entirely due C 2012 The Authors. The Journal of Physiology C 2012 The Physiological Society DOI: 10.1113/jphysiol.2012.229435 4484 S. Severi and others J Physiol 590.18 to increase in theDDslope,with no changes in eitherMDPorTOP.Model testing of BAPTAeffects 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 compatiblewith the observation that If is a major component of pacemaking and rate modulation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.