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Pyridoxal 5\u2032 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Herein, we employed a multipronged approach to investigate PLP\u2019s capability to attenuate CB hyperexcitability in hypertension.<\/jats:p>\n                    <jats:p>First, PLP inhibited Ca2+ responses evoked by \u03b1, \u03b2-methylene ATP in cell lines expressing human (h) P2X3R with an IC50 of 8.7\u2005\u00b5M. 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\u2005\u00b5M; 15\u2005min) attenuated CBs sensory firing in SHR (P = 0.012). Using the in situ working-heart brainstem preparation, carotid artery injections of PLP (1\u20135\u2005mM) attenuated the chemoreflex-evoked sympathetic (P = 0.023) but not phrenic (P = 0.62) responses; the CB was stimulated with potassium cyanide (KCN,50\u2005\u00b5L; 0.04%). In awake telemetered SHR (n = 6), intravenous infusion of PLP (48\u2005mg\/Kg\/h; 30\u2005min) attenuated KCN-evoked chemoreflex responses and reduced systolic, diastolic, and mean blood pressures (\u0394MBP = \u221215.6\u2005mmHg; 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\u2005mg) attenuated the hypoxic ventilatory response only in patients with high peripheral chemoreflex sensitivity (P = 0.021).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf195","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:13:18Z","timestamp":1760530398000},"page":"285-296","source":"Crossref","is-referenced-by-count":2,"title":["Vitamin B6 (Pyridoxal 5\u2032 Phosphate) antagonises carotid body P2X3 receptors in hypertension"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8582-2104","authenticated-orcid":false,"given":"Igor S A","family":"Felippe","sequence":"first","affiliation":[{"name":"Department of Physiology, Manaaki Manawa\u2014The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, 85 Park Road, Grafton, 1023, Auckland ,","place":["New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thalia L","family":"Babbage","sequence":"additional","affiliation":[{"name":"Department of Physiology, Manaaki Manawa\u2014The Centre for Heart Research, Faculty of Medical & Health Sciences, University of Auckland, 85 Park Road, Grafton, 1023, Auckland ,","place":["New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajaa","family":"Shaheen","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of East Anglia , Norwich ,","place":["United 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