The Autonomic Nervous System Can Compensate for Hypocalcemia-Induced Bradycardia in Human and Rabbit Sinoatrial Node Cell Models

Every regular heartbeat is initiated by cyclic spontaneous depolarisations of sinoatrial node cells (SANCs).Altered electrolyte levels, typically occurring in chronic kidney disease (CKD) patients, and the autonomic nervous system (ANS) highly influence pacemaking of the heart.Thus, the effects of sympathetic stimulation and hypocalcemia on the beating rate (BR) were assessed.Therefore, we integrated the -adrenergic (-AR) signalling cascade of Behar et al., into the Severi et al. (rabbit) and Fabbri et al. (human) SANC models.To mimic conditions in patients suffering from CKD, extracellular Ca 2+ ([Ca 2+ ] o ) (0.6 to 1.8 mM) and isoprenaline concentrations ([ISO]) (0.0 to 1000.0 nM) were varied.The extended models predicted that for decreased [Ca 2+ ] o , an exponential-like increase of [ISO] restored the basal BR.In particular, for 1.2 mM [Ca 2+ ] o , 15.5 and 7.3 nM [ISO] for the Severi and Fabbri model restored the initial conditions.With [Ca 2+] o further reduced to 0.6 mM, 60.0 and 41.7 nM [ISO] were required.A sudden loss of sympathetic tone resulted in extreme bradycardia or stopped automaticity.The results suggest that hypocalcemic bradycardia can be compensated by an increased sympathetic tone.The integration of the -AR pathways led to an exponential-like increase of the BR.This combined model may help understanding the pathomechanisms of sudden cardiac death in CKD.