Amplified P2X3 pathway activity in muscle afferent dorsal root ganglion neurons and exercise pressor reflex regulation in hindlimb ischaemia–reperfusion.

Hindlimb ischaemia–reperfusion (IR) is among the most prominent pathophysiological conditions observed in peripheral artery disease (PAD). An exaggerated arterial blood pressure (BP) response during exercise is associated with an elevated risk of cardiovascular events in individuals with PAD. However, the precise mechanisms leading to this exaggerated BP response are poorly elucidated. The P2X3 signalling pathway, which plays a key role in modifying the exercise pressor reflex (EPR), is the focus of the present study. We determined the regulatory role of P2X3 on the EPR in a rat model of hindlimb IR. In vivo and in vitro approaches were used to determine the expression and functions of P2X3 in muscle afferent nerves and EPR in IR rats. We found that in IR rats there was (1) upregulation of P2X3 protein expression in the L4–6 dorsal root ganglia (DRG); (2) amplified P2X currents in isolated isolectin B4 (IB4)‐positive muscle DRG neurons; and (3) amplification of the P2X‐mediated BP response. We further verified that both A‐317491 and siRNA knockdown of P2X3 significantly decreased the activity of P2X currents in isolated muscle DRG neurons. Moreover, inhibition of muscle afferents' P2X3 receptor using A‐317491 was observed to alleviate the exaggerated BP response induced by static muscle contraction and P2X‐induced BP response by α,β‐methylene ATP injection. P2X3 signalling pathway activity is amplified in muscle afferent DRG neurons in regulating the EPR following hindlimb IR. What is the central question of this study?Is the P2X3 signal pathway engaged in the exaggerated exercise pressor reflex (EPR) response in the ischaemia–reperfusion (IR) injury of peripheral artery disease (PAD)?What is the main finding and its importance?IR upregulates expression of the P2X3 receptor and increases the P2X currents in muscle afferent DRG neurons. Pharmacological inhibition using A‐317491 (P2X3 antagonist) and the genetic knockdown of P2X3 reduce the P2X currents in the muscle afferent DRG neurons. A‐317491 also attenuates the exacerbated EPR response following IR.The findings provide evidence that interventions attenuating the P2X3 signalling pathway may enhance tolerance of and adherence to exercise rehabilitation for PAD patients. [ABSTRACT FROM AUTHOR]