P2X3 antagonists as a novel anti-arrhythmic

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Physiology in Focus 2024 (Northumbria University, UK) (2024) Proc Physiol Soc 59, C07

Oral Communications: P2X3 antagonists as a novel anti-arrhythmic

Carol T Bussey1, Rexson Tse1, Martin K Stiles1, David J Paterson1, Julian FR Paton1,

1Manaaki Manawa Centre for Heart Research, Department of Physiology, Faculty of Medical & Health Sciences, University of Auckland Auckland New Zealand, 2Gold Coast Hospital and Health Service, Queensland Health Gold Coast Australia, 3Waikato Clinical School, Faculty of Medical & Health Sciences, University of Auckland Hamilton New Zealand, 4Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Medical Sciences Division, University of Oxford Oxford United Kingdom, 5Manaaki Manawa Centre for Heart Research, Department of Physiology, Faculty of Medical & Health Sciences, University of Auckland Auckland New Zealand,

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Introduction: Cardiovascular diseases are characterised by elevated sympathetic nerve activity, which contributes to end-organ damage, morbidity and mortality. Surgical removal of the stellate ganglion to short-circuit sympathetic nerve overactivity can eradicate arrhythmias, however this is a highly invasive approach with significant side-effects, necessitating discovery of novel non-invasive druggable targets. Recent transcriptomic data shows upregulation of P2X3 purinergic receptors in the stellate ganglia of Spontaneously Hypertensive (SHR) compared to Wistar rats (Bardsley EN et al. 2018. Sci Rep 8, 8633). We hypothesise that these purinergic receptors within cardiac stellate ganglia contribute to sympathetic overactivity and the development of cardiovascular diseases such as hypertension and arrhythmias.

Objectives: Confirm expression of P2X3 receptor in stellate ganglia, investigate cardiac responses to stellate ganglia P2X3 receptor stimulation/inhibition, and examine effect of P2X3 receptor antagonism on cardiac arrhythmias.

Methods: Stellate ganglia from Wistar and SH rats (n=6) and humans (n=2) were immunofluorescently stained for P2X3 receptor and tyrosine hydroxylase, and P2X3 receptor expression in rat stellate ganglia was quantified using qPCR. Cardiac responses to stellate ganglion P2X3 receptors were investigated in the decerebrated working heart-brainstem preparation of Wistar and SH rats (4-5 week old), following anaesthesia with 5% isoflurane in oxygen. Arrhythmias were triggered in SHR, which exhibit increased arrhythmogenicity, with a combination of atropine (30μM) and caffeine (100μM) delivered in the perfusate, followed by electrical stimulation of the stellate ganglion.

Results: We have confirmed in both rat and human stellate ganglia that P2X3 receptors are co-localised with tyrosine hydroxylase-expressing sympathetic cells. P2X3 receptor expression is upregulated in SHR stellate ganglia (Wistar 1.03±0.10, SHR 3.77±0.78 fold, mean±SEM, n=7-8, p<0.01 students t-test). Microinjection of stable ATP analogue αβmethylene-ATP (100μg) directly into the stellate ganglion causes tachycardia (Wistar 45.6±8.3; SHR 62.5±14.1 Δbpm, n=7), which is attenuated by P2X3 inhibition with AF353 (Wistar 25.0±7.5; SHR 19.5±7.5 Δbpm; n=4-5, p<0.05 mixed effects model). Arrhythmias were triggered in the ECG of 61% of experiments (n=13), particularly AV block (n=3), and fragmented QRS complexes (n=4), with bundle block and bradyarrhythmia also observed. Of these arrhythmias, 70% were attenuated or abolished following blockade of P2X3 receptors (n=9).

Conclusions: Stellate ganglion P2X3 purinergic receptors regulate cardiac function, and P2X3 overexpression likely contributes to sympathetic overactivity in cardiovascular disease. P2X3 inhibition rapidly and profoundly recovers arrhythmic heart rhythms, and reverses electrical instability.

Where applicable, experiments conform with Society ethical requirements.

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