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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 \u03b2\u2010adrenergic receptor (\u03b2\u2010AR) signalling cascade, as described by Behar et\u00a0al., was incorporated into the SANC models of Severi et\u00a0al. (rabbit) and Fabbri et\u00a0al. (human). Simulations were conducted across various extracellular calcium ([Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n ) (0.6\u20131.8\u00a0mM) and isoprenaline concentrations [ISO] (0\u20131000\u00a0nM) for a sufficient period of time to allow transient oscillations to equilibrate and reach a limit cycle. The \u03b2\u2010AR cell response of the extended models was validated against new Langendorff\u2010perfused rabbit heart experiments and literature data. The extended models revealed that decreased [Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n necessitated an exponential\u2010like increase in [ISO] to restore the basal BR. Specifically at 1.2\u00a0mM [Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n , the Severi and Fabbri models required 28.0 and 9.6\u00a0nM [ISO], respectively, to restore the initial BR. Further reduction in [Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n to 0.6\u00a0mM required 170.0 and 43.6\u00a0nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n 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 \u03b2\u2010AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n We extended the sinoatrial node cell (SANC) models of Severi et\u00a0al. (rabbit) and Fabbri et\u00a0al. (human) using the \u03b2\u2010adrenergic receptor (\u03b2\u2010AR) signalling cascade Behar et\u00a0al. described.<\/jats:p>\n <\/jats:list-item>\n \n \n Simulations were conducted across various extracellular calcium ([Ca\n 2+<\/jats:sup>\n ]\n o<\/jats:sub>\n ) (0.6\u20131.8\u00a0mM) and isoprenaline concentrations [ISO] (0\u20131000\u00a0nM) to reflect conditions in haemodialysis (HD) patients.\n <\/jats:p>\n <\/jats:list-item>\n \n An exponential\u2010like increase in [ISO] compensated for hypocalcaemia\u2010induced bradycardia in both models, whereas interspecies differences increased the sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone.<\/jats:p>\n <\/jats:list-item>\n \n The 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.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp287557","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T11:10:29Z","timestamp":1741691429000},"page":"5236-5259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sympathetic stimulation can compensate for hypocalcaemia\u2010induced bradycardia in human and rabbit sinoatrial node cells"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1228-159X","authenticated-orcid":false,"given":"Moritz","family":"Linder","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering Karlsruhe Institute of Technology (KIT) Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Stary","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering Karlsruhe Institute of Technology (KIT) Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergo\u030b","family":"Bitay","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Albert Szent\u2010Gy\u00f6rgyi Medical School University of Szeged Szeged Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Albert Szent\u2010Gy\u00f6rgyi Medical School University of Szeged Szeged Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-4744","authenticated-orcid":false,"given":"Axel","family":"Loewe","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering Karlsruhe Institute of Technology (KIT) Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"e_1_2_6_2_1","unstructured":"American Heart Association. 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