title: Isoprenaline: a potential contributor in sick sinus syndrome--insights from a mathematical model of the rabbit sinoatrial node.
abstract: The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca²⁺ transient, and i(Na) changes induced by SCN5A gene mutations; the cell models were also incorporated into an intact SAN-atrium model of the rabbit heart that is based on both heterogeneities of the SAN electrophysiology and histological structure. Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase in i(Na) and i(Ca,T) which were reduced by the mutation.
authors.affiliation: Department of Physics and Institute of Theoretical Physics and Astrophysics, Xiamen University, Xiamen 361005, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Physics and Electronic Information, Anhui Normal University, Wuhu 241000, China ; Biological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester M139PL, UK.
authors.forename: Ji-qian
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: Department of Physics and Institute of Theoretical Physics and Astrophysics, Xiamen University, Xiamen 361005, China.
authors.forename: Jian-wei
authors.initials: JW
authors.lastname: Shuai
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008955:Models, Cardiovascular; D009154:Mutation; D011817:Rabbits; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D061566:Voltage-Gated Sodium Channels; D007545:Isoproterenol