Effects of bradykinin on voltage-gated KV 4 channels in muscle dorsal root ganglion neurons of rats with experimental peripheral artery disease

Abstract

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.

Abstract: 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.

Keywords: A-type voltage-gated K+ channels; bradykinin; dorsal root ganglion; peripheral artery disease.