Felippe, Igor S. A., Babbage, Thalia L., Shaheen, Rajaa, Bassetto, Marcella  ORCID: https://orcid.org/0000-0002-2491-5868, 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.
2025.
Vitamin B6 (pyridoxal 5’ phosphate) antagonizes carotid body P2X3 receptors in hypertension.
Cardiovascular Research
122
(2)
, pp. 285-296.
10.1093/cvr/cvaf195
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Abstract
Aims ATP acting on 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, is reported as being a non-selective P2X receptor blocker. Hence, we hypothesized 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 cells lines expressing human (h) P2X3R with IC50 of 8.7µM. 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 (1-5mM) 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 randomized 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 antagonizes P2X3R and is a viable candidate for larger clinical trials to treat CB dysregulation in cardiovascular diseases.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Pharmacy |
| Additional Information: | License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by-nc/4.0/, Start Date: 2025-10-16 |
| Publisher: | Oxford University Press |
| ISSN: | 0008-6363 |
| Date of First Compliant Deposit: | 11 November 2025 |
| Date of Acceptance: | 17 September 2025 |
| Last Modified: | 01 Apr 2026 14:00 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/181920 |
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