Effects of bradykinin on voltage-gated KV4 channels in muscle dorsal root ganglion neurons of rats with experimental peripheral artery disease

Key points During exercise, bradykinin (BK), a muscle metabolite in ischaemic muscles, exaggerates autonomic responses to activation of muscle afferent nerves in peripheral artery disease (PAD). We examined whether BK inhibits activity of K(V)4 channels in muscle afferent neurons of PAD rats induced by femoral artery occlusion. We demonstrated that: 1) femoral occlusion attenuates K(V)4 currents in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles and decreases the threshold of action potential firing; 2) BK has a greater inhibitory effect on K(V)4 currents in muscle DRG neurons of PAD rats; and 3) expression of K(V)4.3 is downregulated in DRGs of PAD rats and inhibition of K(V)4.3 significantly decreases activity of K(V)4 currents in muscle DRG neurons. Femoral artery occlusion-induced limb ischaemia and/or ischaemia-induced metabolites (i.e. BK) inhibit activity of K(V)4 channels in muscle afferent neurons and this is likely involved in the exaggerated exercise pressor reflex in PAD. Muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses are exaggerated during exercise in patients with peripheral artery diseases (PAD) and in PAD rats induced by femoral artery occlusion. However, the precise signalling pathways and molecular mediators responsible for these abnormal autonomic responses in PAD are poorly understood. A-type voltage-gated K+ (K-V) channels are quintessential regulators of cellular excitability in the various tissues. Among K-V channels, K(V)4 (i.e. K(V)4.1 and K(V)4.3) in primary sensory neurons mainly participate in physiological functions in regulation of mechanical and chemical sensation. However, little is known about the role of K(V)4 in regulating neuronal activity in muscle afferent neurons of PAD. In addition, bradykinin (BK) is considered as a muscle metabolite contributing to the exaggerated exercise pressor reflex in PAD rats with femoral artery occlusion. Our data demonstrated that: 1) K(V)4 currents are attenuated in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles of PAD rats, along with a decreasing threshold of action potential firing; 2) K(V)4 currents are inhibited by application of BK onto muscle DRG neurons of PAD rats to a greater degree; and 3) expression of K(V)4.3 is downregulated in the DRGs of PAD rats and K(V)4.3 channel is a major contributor to the activity of K(V)4 currents in muscle DRG neurons. In conclusion, data suggest that femoral artery occlusion-induced limb ischaemia and/or ischaemia-induced metabolites (i.e. BK) inhibit the activity of K(V)4 channels in muscle afferent neurons likely leading to the exaggerated exercise pressor reflex observed in PAD.

Automated summary

The study demonstrates that in patients with PAD, muscle afferent neurons are inhibited by the metabolite bradykinin (BK), leading to a decrease in activity of K(V)4 channels and possibly exaggerating the exercise pressor reflex in PAD.