Voltage-Gated Potassium Channel Dysfunction in Dorsal Root Ganglia Contributes to the Exaggerated Exercise Pressor Reflex in Rats with Chronic Heart Failure

An exaggerated exercise pressor reflex (EPR) causes excessive sympatho-excitation and exercise intolerance during physical activity in the chronic heart failure (CHF) state. Muscle afferent sensitization contributes to the genesis of the exaggerated EPR in CHF. However, the cellular mechanisms underlying muscle afferent sensitization in CHF remain unclear. Considering that voltage-gated potassium (Kv) channels critically regulate afferent neuronal excitability, we examined the potential role of Kv channels in mediating the sensitized EPR in male CHF rats. Real time RT-PCR and western blotting experiments demonstrate that both mRNA and protein expressions of multiple Kv channel isoforms (Kv1.4, Kv3.4, Kv4.2 and Kv4.3) were downregulated in lumbar DRGs of CHF rats compared to sham rats. Immunofluorescence data demonstrates significant decreased Kv channel staining in both NF200-positive and IB4-positive lumbar DRG neurons in CHF rats compared to sham rats. Data from patch clamp experiments demonstrate that the total Kv current, especially IA, was dramatically decreased in medium-sized IB4-negative muscle afferent neurons (a subpopulation containing mostly Aδ neurons) from CHF rats compared to sham rats, indicating a potential functional loss of Kv channels in muscle afferent Aδ neurons. In in vivo experiments, adenoviral overexpression of Kv4.3 in lumbar DRGs for one week attenuated the exaggerated EPR induced by muscle static contraction and the mechanoreflex by passive stretch without affecting the blunted cardiovascular response to hindlimb arterial injection of capsaicin in CHF rats. These data suggest that Kv channel dysfunction in DRGs play a critical role in mediating the exaggerated EPR and muscle afferent sensitization in CHF.

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. KV7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified KV7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the KV7 activator retigabine, and block by KV7 specific inhibitor XE991. The block of KV7 current by different XE991 concentrations suggests that the KV7 current is comprised of both KV7.2/7.3 (high affinity) and KV7.5 (low affinity) channels. The KV7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and IV afferents. The inhibition of KV7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that KV7 channel activators such as retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease.

Goal-dependent tuning of muscle spindle receptors during movement preparation

Voluntary movements are believed to undergo preparation before they are executed. Preparatory activity can benefit reaction time and the quality of planned movements, but the neural mechanisms at work during preparation are unclear. For example, there are no overt changes in muscle force during preparation. Here, using an instructed-delay manual task, we demonstrate a decrease in human muscle afferent activity (primary spindles) when preparing to reach targets in directions associated with stretch of the spindle-bearing muscle. This goal-dependent modulation of proprioceptors began early after target onset but was markedly stronger at the latter parts of the preparatory period. Moreover, whole-arm perturbations during reach preparation revealed a modulation of stretch reflex gains (shoulder and upper arm muscles) that reflected the observed changes in spindle activity. We suggest that one function of central preparatory activity is to tune muscle stiffness according to task goals via the independent control of muscle spindle sensors.