K7 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. K7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified K7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the K7 activator retigabine, and block by K7 specific inhibitor XE991. The blocking of K7 current by different XE991 concentrations suggests that the K7 current is generated by both K7.2/7.3 (high affinity) and K7.5 (low affinity) channels. The K7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and group IV afferents. The inhibition of K7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that K7 channel activators such as retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease. K7 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 K7 current is generated by K7.2/3 and K7.5 channels. The BK inhibition of K7 channels may explain how BK activates the exercise pressor reflex (EPR). Retigabine can enhance K7 current, which could help control the inappropriately activated EPR in patients with cardiovascular disease.