["The Journal of Physiology, Volume 604, Issue 13, Page 5236-5259, 1 July 2026. ", "\nAbstract figure legend AC: adenylyl cyclase, APT: adenosine triphosphate, AMP: adenosine monophosphate, cAMP: cyclic adenosine monophosphate, PDE: phosphodiesterase, PKA: protein kinase A, PPT: protein phosphatase, P: phosphorylation, RyR: ryanodine receptor, SERCA: sarcoplasmic/endoplasmic reticulum Ca2+‐adenosine triphosphatase, SR: sarcoplasmic reticulum, β‐AR: β‐adrenergic receptor, [Ca2+]i/o: intra‐/extracellular calcium concentration, [Ca2+]jsr/nsr: junctional/network sarcoplasmic reticulum calcium concentration, [Ca2+]sub: subsarcolemmal calcium concentration, ChR: cholinergic receptor, [K+]i/o: intra‐/extracellular potassium concentration, [Na+]i/o: intra‐/extracellular sodium concentration, [ISO]: isoprenaline concentration, ICaL: L‐type Ca2+ current, ICaT: T‐type Ca2+ current, If: hyperpolarisation‐activated ‘funny’ current, IK,ACh: acetylcholine‐activated K+ current, IKr: rapidly activating delayed rectifier current, IKs: slowly activating delayed rectifier current, IKur: ultra‐rapid activating delayed rectifier current, INaCa: Na+/Ca2+ exchanger current, INaK: Na+/K+ pump current, INa: Na+ current, Ito: transient outward K+ current, Jdiff: Ca2+ diffusion flux from submembrane space to myoplasm, Jrel: Ca2+ release flux from SR via RyRs, Jtr: Ca2+ diffusion flux from the network to junctional SR, Jup: Ca2+ uptake by SR.\n\n\n\n\n\n\n\n\n\nAbstract\nRegular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANCs). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus we investigated the effects of hypocalcaemia and sympathetic stimulation on the SANC beating rate (BR). The β‐adrenergic receptor (β‐AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca2+]o) (0.6–1.8 mM) and isoprenaline concentrations [ISO] (0–1000 nM) for a sufficient period of time to allow transient oscillations to equilibrate and reach a limit cycle. The β‐AR cell response of the extended models was validated against new Langendorff‐perfused rabbit heart experiments and literature data. The extended models revealed that decreased [Ca2+]o necessitated an exponential‐like increase in [ISO] to restore the basal BR. Specifically at 1.2 mM [Ca2+]o, the Severi and Fabbri models required 28.0 and 9.6 nM [ISO], respectively, to restore the initial BR. Further reduction in [Ca2+]o to 0.6 mM required 170.0 and 43.6 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca2+]o resulted in a loss of automaticity within seconds. These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the β‐AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients.\n\n\n\n\n\n\n\n\n\nKey points\n\nWe extended the sinoatrial node cell (SANC) models of Severi et al. (rabbit) and Fabbri et al. (human) using the β‐adrenergic receptor (β‐AR) signalling cascade Behar et al. described.\nSimulations were conducted across various extracellular calcium ([Ca2+]o) (0.6–1.8 mM) and isoprenaline concentrations [ISO] (0–1000 nM) to reflect conditions in haemodialysis (HD) patients.\nAn exponential‐like increase in [ISO] compensated for hypocalcaemia‐induced bradycardia in both models, whereas interspecies differences increased the sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone.\nThe extended models may help to further understand the pathomechanisms of several cardiovascular diseases affecting pacemaking, such as the high occurrence of sudden cardiac death (SCD) in chronic kidney disease (CKD) patients.\n\n\n"]