K V 7 Channels are Potential Regulators of the Exercise Pressor Reflex

Abstract

The exercise pressor reflex (EPR) is a peripheral neural reflex that originates in skeletal muscle and is activated by exercise-induced signals to increase arterial blood pressure, ventilation, and cardiac output. Muscle ischemia can elicit the EPR, which can be inappropriately activated in patients with peripheral vascular disease and heart disease to increase the incidence of myocardial infarction. The goal of this research was to better understand the receptor/channels that control excitability of group III and group IV muscle afferent fibers that give rise to the EPR. Certain chemicals such as bradykinin are released within contracting muscle and enhance the excitability of group III/IV afferents to evoke the EPR. However, the mechanism by which bradykinin elicits the EPR is unknown. KV7 channels strongly regulate neuronal excitability and have been shown to be modulated by bradykinin. We have identified KV currents in identified muscle afferents by their characteristic activation/deactivation kinetics and block by KV7 specific inhibitor XE991. The KV7 current was also inhibited by 300 nM bradykinin. A KV7 channel antibody labeled group IV muscle afferent fibers within muscle, which demonstrated axonal expression of these channels. KV7 likely modulates the EPR. The inhibition of KV7 by bradykinin could be a mechanism by which this metabolic mediator enhances EPR excitability. Furthermore, our results suggest that the recently FDA approved KV7 activator, retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease. This study is funded by NIH grant AR059397 and the ATSU-KCOM Graduate Program Committee.