Vitamin B6 (Pyridoxal 5' Phosphate) antagonises carotid body P2X3 receptors in hypertension.

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.