Untangling purinergic regulation through the stellate ganglion

Sympathetic nerve overactivity is a key contributor to cardiovascular diseases, and related morbidity and mortality. Denervation of the stellate ganglion has been explored as a therapeutic strategy for heart failure, but there is a need for targeted, non-invasive approaches. Upregulation of P2X3 purinergic receptors in stellate ganglia of Spontaneously Hypertensive (SHR) compared to Wistar rats (16-week-old), revealed by RNASeq transcriptional profiling, leads us to hypothesize that purinergic signalling may play a role in the excessive sympathetic drive to the heart in cardiovascular disease.Cardiac effects of stellate ganglion purinergic stimulation were investigated in the working heart-brainstem preparation of Wistar rats (4-5 week old). Microinjection of ATP (100ng) directly into the right stellate ganglion increased heart rate (Wistar 13±6 Δbpm, n=6; SHR 25±8 Δbpm, n=2). This tachycardia was attenuated by either systemic P2X3 inhibition with AF-353 (Wistar 2±2 Δbpm, n=4), or abolished by denervation of the cardiac sympathetic nerve emanating from the stellate ganglion. However, bradycardic responses were also observed (Wistar -24 ± 12 bpm, n=5), likely indicating contrasting signalling by purinergic components such as adenosine.These findings were echoed in isolated post-ganglionic sympathetic neurones from the stellate ganglia of Wistar rats (4-6 weeks), wherein ATP evoked a significant increase (Median; 0.21) in [Ca 2+ ] i as measured by Fura-2AM imaging (n=15, Wilcoxon matched-pairs test; p<0.0001) with a high degree of variability suggestive of responding and non-responding cells. This ATP-induced calcium transient was inhibited by specific P2X3 receptor antagonism with either NF-10 or AF-130.Further, immunofluorescence analysis shows clustering of neurones expressing P2X3 within the stellate ganglion.Stellate ganglion P2X3 purinergic receptors contribute to cardiac chronotropic regulation, with apparent heterogeneity in neuronal expression and differential purinergic responses. P2X3 receptor overexpression is likely to contribute to cardiac sympathetic overactivity and hypertension, making them a promising novel therapeutic target. Funding: Support provided by Health Research Council of New Zealand. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.