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ToolsFelippe, Igor S.A., Babbage, Thalia L., Shaheen, Rajaa, Bassetto, Marcella, Fan, Jui Lin, Pauza, Audrys, Gold, Olivia, Thakkar, Pratik, Dawes, Matthew, Bates, Melissa L., McBryde, Fiona, Fountain, Samuel J., Fisher, James P. and Paton, Julian F.R. (2026) Vitamin B6 (Pyridoxal 5′ Phosphate) antagonises carotid body P2X3 receptors in hypertension. Cardiovascular Research, 122 (2). pp. 285-296. ISSN 0008-6363
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Abstract
Aims: ATP acting on P2X3 receptors (P2X3R) within carotid bodies (CBs) underpins chemoreflex-mediated sympathetic overactivity in spontaneously hypertensive rats (SHR). Pyridoxal 5′ phosphate (PLP), the active form of vitamin B6, has been reported to act as a non-selective P2X receptor blocker. Hence, we hypothesised that PLP antagonism of P2X3R in the CB would treat hypertension. Methods and results: Herein, we employed a multipronged approach to investigate PLP’s capability to attenuate CB hyperexcitability in hypertension. First, PLP inhibited Ca2+ responses evoked by α, β-methylene ATP in cell lines expressing human (h) P2X3R with an IC50 of 8.7 µM. Next, in-silico data predicted that PLP binds to the same site of Gefapixant, supporting an allosteric antagonism. Using an isolated perfused carotid artery bifurcation-CB preparation, arterial infusion of PLP (50 µM; 15 min) attenuated CBs sensory firing in SHR (P = 0.012). Using the in situ working-heart brainstem preparation, carotid artery injections of PLP (1–5 mM) attenuated the chemoreflex-evoked sympathetic (P = 0.023) but not phrenic (P = 0.62) responses; the CB was stimulated with potassium cyanide (KCN,50 µL; 0.04%). In awake telemetered SHR (n = 6), intravenous infusion of PLP (48 mg/Kg/h; 30 min) attenuated KCN-evoked chemoreflex responses and reduced systolic, diastolic, and mean blood pressures (ΔMBP = −15.6 mmHg; P = 0.025). Translating our results, we performed a small double-blind, randomised clinical trial. In volunteers with hypertension (n = 14), oral supplementation with pyridoxine hydrochloride (600 mg) attenuated the hypoxic ventilatory response only in patients with high peripheral chemoreflex sensitivity (P = 0.021). Conclusion: Our findings suggest that PLP binds to and antagonises P2X3R and is a viable candidate for larger clinical trials to treat CB dysregulation in cardiovascular diseases.
| Item Type: | Article |
|---|---|
| Additional Information: | Data availability: The authors declare that all supporting data have been made publicly available at Figshare and can be accessed using DOI (http://dx.doi.org/10.17608/k6.auckland.28191725). Raw data is available from the corresponding author upon reasonable request. |
| Uncontrolled Keywords: | carotid body,chemoreflex,hypertension,p2x3 receptors,pyridoxal 5′ phosphate,vitamin b6,physiology,cardiology and cardiovascular medicine,physiology (medical),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1314 |
| Faculty \ School: | Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Science > Research Groups > Cells and Tissues |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 13 May 2026 15:34 |
| Last Modified: | 14 May 2026 15:16 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/103009 |
| DOI: | 10.1093/cvr/cvaf195 |
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