Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA058

Poster Communications

A shift in the atrial expression of voltage-gated sodium channels is seen in old age with Nav1.5 declining and Nav1.8 increasing - a prelude to atrial fibrillation.

S. Cooper1, M. K. Lancaster2, S. A. Jones1

1. University of Hull, Hull, United Kingdom. 2. University of Leeds, Leeds, United Kingdom.

The cardiac voltage-gated sodium channel (VGSC) isoform, Nav1.5, is primarily responsible for the fast sodium current (INa) which underlies the upstroke of the cardiac action potential (AP) and determines cellular excitability. Recently, the ‘non-cardiac' VGSC isoform Nav1.8 has been detected in the heart, where it plays a critical role in the initiation and maintenance of AF. AF is an age-associated problem with the majority of cases presenting in the elderly. Therefore, we investigated age-associated remodelling of Nav1.5 and Nav1.8 VGSC isoforms in the right atria. We examined atrial tissue from young (6 months of age) and old (24 months of age) Wistar rats. Right atrial cryosections were triple labelled with pre-conjugated complexes of anti-Nav1.5 (Alomone, Israel) to Alexa 488 (ThermoFisher Scientific, UK), anti-Nav1.8 to Alexa 555 and anti-desmin to Alexa 647 viewed by confocal microscopy (LSM710 Zeiss, UK). Western blot was conducted of right atrial tissue homogenates with the same primary antibodies conjugated to HRP. Microelectrode impalements of tissue from young and old rats were used to record atrial APs. All procedures were conducted with University of Hull ethical approval and in accordance with current UK legislation. Data are mean ± SEM, n = number of rats per group, analysed by Student's t-test or ANOVA with significance at p<0.05. Fluorescent labelled Nav1.8 protein was observed as striated labelling, co-expressed with Nav1.5 labelled protein, predominantly at t-tubules of atrial myocytes as determined by labelled desmin protein: a novel finding of subcellular distribution. Nav1.5 immunofluorescent labelled protein was significantly reduced from 100 ± 11.8 % in the young to 61 ± 8.4 % in the old rat (n=5; t-test p=0.01), whereas Nav1.8 protein fluorescence significantly increased by 25% in the old rat (100 ± 3.6 % young vs. 125 ± 6.3 % old; t-test p=0.02). Western blot analysis showed a similar significant reduction of Nav1.5 protein expression by 50 % in the old rat (100 ± 12.3 % young vs. 50 ± 8.7% old; n=5; ANOVA p=0.03), with a significant increase in Nav1.8 protein expression of 57 % in the old rat (100 ± 6.7 % young vs. 157 ± 22.2 % old; n=6; ANOVA p=0.02). The atrial AP amplitude significantly reduced from 105 ± 12 mV (young, n=6) to 74 ± 8 mV in the old rat (n=7) (t-test p=0.04). In conclusion, we found loss of Nav1.5 protein from the right atria but an increase in Nav1.8 in old rats. These changes associate with significant changes in the atrial action potential. Such remodelling is likely to underpin the reduction in fast INa and increased late INa observed in AF and may be a key contributing factor to the increased prevalence of AF in the elderly. Manipulation of this shift or the individual isoforms may prove useful for treatment or prevention of AF.

Where applicable, experiments conform with Society ethical requirements