title: Characterization and influence of cardiac background sodium current in the atrioventricular node.
abstract: Background inward sodium current (IB,Na) that influences cardiac pacemaking has been comparatively under-investigated. The aim of this study was to determine for the first time the properties and role of IB,Na in cells from the heart's secondary pacemaker, the atrioventricular node (AVN). Myocytes were isolated from the AVN of adult male rabbits and mice using mechanical and enzymatic dispersion. Background current was measured using whole-cell patch clamp and monovalent ion substitution with major voltage- and time-dependent conductances inhibited. In the absence of a selective pharmacological inhibitor of IB,Na, computer modelling was used to assess the physiological contribution of IB,Na. Net background current during voltage ramps was linear, reversing close to 0mV. Switching between Tris- and Na(+)-containing extracellular solution in rabbit and mouse AVN cells revealed an inward IB,Na, with an increase in slope conductance in rabbit cells at -50mV from 0.54±0.03 to 0.91±0.05nS (mean±SEM; n=61 cells). IB,Na magnitude varied in proportion to [Na(+)]o. Other monovalent cations could substitute for Na(+) (Rb(+)>K(+)>Cs(+)>Na(+)>Li(+)). The single-channel conductance with Na(+) as charge carrier estimated from noise-analysis was 3.2±1.2pS (n=6). Ni(2+) (10mM), Gd(3+) (100μM), ruthenium red (100μM), or amiloride (1mM) produced modest reductions in IB,Na. Flufenamic acid was without significant effect, whilst La(3+) (100μM) or extracellular acidosis (pH6.3) inhibited the current by >60%. Under the conditions of our AVN cell simulations, removal of IB,Na arrested spontaneous activity and, in a simulated 1D-strand, reduced conduction velocity by ~20%. IB,Na is carried by distinct low conductance monovalent non-selective cation channels and can influence AVN spontaneous activity and conduction.
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: Jue
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: James
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: Shin
authors.initials: S
authors.lastname: Inada
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Stéphanie C M
authors.initials: SC
authors.lastname: Choisy
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Orchard
authors.affiliation: Department of Physics and Astronomy, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
authors.affiliation: School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK. Electronic address: jules.hancox@bristol.ac.uk.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D000818:Animals; D001283:Atrioventricular Node / Q000502:physiology*; D003198:Computer Simulation; D055724:Electrophysiological Phenomena; D008297:Male; D051379:Mice; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*
chemical_list: D012964:Sodium
keywords: AVN; Atrioventricular node; Background current; I(B,Na); Pacemaking