Vitamin B6 (pyridoxal 5’ phosphate) antagonizes carotid body P2X3 receptors in hypertension

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 , cvaf195. 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:	Published Online
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
Last Modified:	27 Oct 2025 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/181920

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