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 0 mV. 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 − 50 mV from 0.54 ± 0.03 to 0.91 ± 0.05 nS (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 ± 1.2 pS (n = 6). Ni2 + (10 mM), Gd3 + (100 μM), ruthenium red (100 μM), or amiloride (1 mM) produced modest reductions in IB,Na. Flufenamic acid was without significant effect, whilst La3 + (100 μM) or extracellular acidosis (pH 6.3) 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.

Propagation Failure by TRPM4 Overexpression

“…Our assignment of I Nab to TRPM4 channels is in contrast to Cheng et al (19) who found that TRPM4 channel was not responsible for I Nab in mouse and rabbit AVN. However, expression of TRPM4 channels may differ across species and tissue type.…”

“…For first-and second-degree blocks, the disruption would have to be quite proximal in the His bundle, otherwise impulses from the atrioventricular node (AVN) could still arrive early in the ventricles. Cheng et al (19) concluded that I Nab in the AVN of rabbits was not TRPM4 current. However, the full expression profile of TRPM4 channels across tissue and species has yet to be performed, so we do not know if TRPM4 channels are in human AVN.…”

Cardiac background sodium current: Elusive but important

“…6 AVN I B,Na is time-independent, shows GHK voltage-dependence and closely resembles that reported for the SAN. 4,6 The underlying channels show poor monovalent cation selectivity with an Eisenmann III (Rb C > K C > Cs C > Na C > Li C ) permeability sequence. To our knowledge, this new study also provides, for the first time for any cardiac region, an estimate of single channel conductance for the nonselective cation channels (NSCCs) mediating I B,Na .…”

“…This year, attention has again been drawn to I B,Na through work on cells from the heart's secondary pacemaker, the AVN. 6 Using conditions which inhibited major voltage and time-dependent conductances, Cheng and colleagues have isolated I B,Na for the first time from AVN cells of 2 model species (rabbit and mouse). 6 AVN I B,Na is time-independent, shows GHK voltage-dependence and closely resembles that reported for the SAN.…”

“…6 Using conditions which inhibited major voltage and time-dependent conductances, Cheng and colleagues have isolated I B,Na for the first time from AVN cells of 2 model species (rabbit and mouse). 6 AVN I B,Na is time-independent, shows GHK voltage-dependence and closely resembles that reported for the SAN. 4,6 The underlying channels show poor monovalent cation selectivity with an Eisenmann III (Rb C > K C > Cs C > Na C > Li C ) permeability sequence.…”