KV7 channels are potential regulators of the exercise pressor reflex

The exercise pressor reflex (EPR) originates in skeletal muscle and is activated by exercise-induced signals to increase arterial blood pressure and cardiac output. Muscle ischemia can elicit the EPR, which can be inappropriately activated in patients with peripheral vascular disease or heart failure to increase the incidence of myocardial infarction. We seek to better understand the receptor/channels that control excitability of group III and group IV muscle afferent fibers that give rise to the EPR. Bradykinin (BK) is released within contracting muscle and can evoke the EPR. However, the mechanism is incompletely understood. K(V)7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified K(V)7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the K(V)7 activator retigabine, and block by K(V)7 specific inhibitor XE991. The blocking of K(V)7 current by different XE991 concentrations suggests that the K(V)7 current is generated by both K(V)7.2/7.3 (high affinity) and K(V)7.5 (low affinity) channels. The K(V)7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and group IV afferents. The inhibition of K(V)7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that K(V)7 channel activators such as retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease. NEW & NOTEWORTHY K(V)7 channels control neuronal excitability. We show that these channels are expressed in muscle afferents and generate currents that are blocked by XE991 and bradykinin (BK). The XE991 block suggests that K(V)7 current is generated by K(V)7.2/3 and K(V)7.5 channels. The BK inhibition of K(V)7 channels may explain how BK activates the exercise pressor reflex (EPR). Retigabine can enhance K(V)7 current, which could help control the inappropriately activated EPR in patients with cardiovascular disease.

Automated summary

The exercise pressor reflex (EPR) originates in skeletal muscle and is activated by signals during exercise to increase arterial blood pressure. Muscle ischemia can inappropriately activate the EPR in patients with peripheral vascular disease or heart failure. K(V)7 channels in muscle afferents are regulated by bradykinin (BK) and may play a role in EPR activation. Retigabine, a K(V)7 channel activator, could potentially help reduce the exacerbated EPR in patients with cardiovascular disease.