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

ABSTRACT Background: ATP acting on P2X3 receptors (P2X3R) within carotid bodies (CBs) underpins chemoreflex-mediated sympathetic overactivity in Spontaneously Hypertensive rats (SHR). Given that pyridoxal 5’phosphate (PLP), the active form of vitamin B6 (pyridoxine hydrochloride; PHC), is a non-selective P2X receptor blocker, we hypothesized that PLP antagonism in the CB of SHR would lower blood pressure in hypertension. Methods: Herein, we employed in silico, in vitro, in situ and in vivo models to investigate the capability of PLP to bind to P2X3R to attenuate CB hyperexcitability in SHR. We performed a double-blind randomized clinical trial to investigate the capability of PLP to attenuate CB hyperexcitability in hypertensive patients. Results: First, PLP inhibited Ca2+ responses evoked by α,β-methylene ATP in cells lines expressing human (h) P2X2/3R with IC50 of 8.7µM (N=5). It also significantly increased the EC50 of α,β-methylene ATP from 433 nM to 1706 nM (P