Uncovering Anti-Arrhythmic Potential of Stellate Ganglion Purinergic Receptors.

Cardiovascular disease affects over 30% of people worldwide and is one of the leading causes of death each year. Elevated sympathetic nerve activity is a common feature of cardiovascular disease, contributing to end-organ damage, morbidity and mortality. Recent findings indicate that short-circuiting sympathetic nerve overactivity by removal of the stellate ganglion can eradicate arrhythmias, emphasising the need for novel therapeutic targets to correct signalling non-invasively. We have revealed upregulation of the P2X3 purinergic receptor in stellate ganglia of Spontaneously Hypertensive (SHR) compared to Wistar rats (16 week-old), via RNASeq transcriptional profiling. We hypothesise that these purinergic receptors within cardiac stellate ganglia play a role in the excessive sympathetic drive to the heart in cardiovascular disease and can initiate cardiac arrhythmias. Thus, we have investigated the functional role of purinergic receptors in the stellate ganglion. Administration of ATP to acutely isolated post-ganglionic sympathetic neurones from the stellate ganglia of Wistar rats (4-6 week-old) evokes a significant increase (Median; 0.21) in [Ca ] as measured by Fura-2AM imaging (n=15, Wilcoxon matched-pairs test; p<0.0001). This ATP-induced calcium transient was inhibited by specific P2X3 receptor antagonism with either NF-10 or AF-130. Cardiac effects of stellate ganglion purinergic stimulation were investigated in the working heart-brainstem preparation of Wistar rats (4-6 week-old). Increasing doses of ATP (50-250 µg) delivered via microinjection (50-250 µL) directly to the right stellate ganglion produced either a tachycardia (18 ± 6 bpm, n=6) or bradycardia (-24 ± 12 bpm, n=5); these responses were typically found at distinct sites within the ganglion. Preliminary data from SHR suggest that higher doses of ATP (≥250µg) may be arrhythmogenic (n=3). P2X3 purinergic receptors are present in the sympathetic stellate ganglion and contribute to calcium ion flux and cardiac chronotropic regulation. Overexpression of P2X3 receptors is likely to contribute to excessive cardiac sympathetic activity and the development of hypertension and cardiac arrhythmias, making them a promising novel therapeutic target.