K_V7 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_V7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified K_V7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the K_V7 activator retigabine, and block by K_V7 specific inhibitor XE991. The blocking of K_V7 current by different XE991 concentrations suggests that the K_V7 current is generated by both K_V7.2/7.3 (high affinity) and K_V7.5 (low affinity) channels. The K_V7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and group IV afferents. The inhibition of K_V7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that K_V7 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_V7 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_V7 current is generated by K_V7.2/3 and K_V7.5 channels. The BK inhibition of K_V7 channels may explain how BK activates the exercise pressor reflex (EPR). Retigabine can enhance K_V7 current, which could help control the inappropriately activated EPR in patients with cardiovascular disease.