Novel role for purinergic 2× subtype 4 (P2X4) receptors in the exercise pressor reflex and mechanoreflex: Effect of heart failure

Abstract

We investigated the role played by ATP-sensitive purinergic 2 × 4 (P2X4) receptors on the sensory endings of thin fibre muscle afferents in exercise pressor reflex and mechanoreflex activation in healthy/SHAM rats and rats with heart failure with reduced ejection fraction (HF-rEF). We hypothesized that infusion of the P2X4 receptor antagonist 5-BDBD (8 μg) into the hindlimb arterial supply would reduce the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to 30s of electrically-induced hindlimb skeletal muscle contraction (model of exercise pressor reflex activation) and 30s of hindlimb skeletal muscle stretch (model of mechanoreflex activation) in decerebrate, unanesthetized HF-rEF rats but not SHAM rats. Ejection fraction was significantly lower in HF-rEF (46 ± 3 %) compared to SHAM (83 ± 2 %; P < 0.001) rats. In SHAM rats, P2X4 receptor blockade had no effect on the pressor response to hindlimb muscle contraction (n = 8) or the pressor and RSNA response to muscle stretch (n = 4). However, in SHAM rats we found that P2X4 receptor blockade significantly reduced the RSNA response to muscle contraction. In HF-rEF rats, P2X4 receptor blockade reduced the pressor and RSNA response to hindlimb muscle contraction (n = 7) as well as the pressor, but not the RNSA, response to hindlimb muscle stretch (n = 8). Collectively, the data suggest that P2X4 receptors on thin fibre muscle afferent sensory endings play a role in the evoking the exercise pressor reflex in healthy subjects that is limited to RSNA, and that in HF-rEF this expands to a significant role in mechanoreflex and exercise pressor reflex-mediated blood pressure control.

Keywords: Exercise pressor reflex; Heart failure reduced ejection fraction; Muscle afferents; P2X4.