1. Voltage-gated potassium channel dysfunction in dorsal root ganglia contributes to the exaggerated exercise pressor reflex in rats with chronic heart failure
- Author
-
Eric Lazartigues, Hanjun Wang, Lie Gao, Yanhui Cai, Juan Hong, and Shubin Fu
- Subjects
Male ,0301 basic medicine ,Dorsum ,medicine.medical_specialty ,Patch-Clamp Techniques ,Physiology ,Potassium ,chemistry.chemical_element ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Ganglia, Spinal ,Physiology (medical) ,Internal medicine ,Reflex ,medicine ,Animals ,Neurons, Afferent ,Myocardial infarction ,Muscle, Skeletal ,Sensitization ,Ion channel ,Heart Failure ,Afferent Pathways ,Exercise Tolerance ,Reflex, Abnormal ,business.industry ,Voltage-gated potassium channel ,medicine.disease ,Rats ,Disease Models, Animal ,Shal Potassium Channels ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Shaw Potassium Channels ,chemistry ,Potassium Channels, Voltage-Gated ,Heart failure ,Kv1.4 Potassium Channel ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Research Article - Abstract
An exaggerated exercise pressor reflex (EPR) causes excessive sympathoexcitation 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 rats with CHF. Real-time reverse transcription-polymerase chain reaction (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 dorsal root ganglions (DRGs) of CHF rats compared with sham rats. Immunofluorescence data demonstrate significant decreased Kv channel staining in both NF200-positive and IB4-positive lumbar DRG neurons in CHF rats compared with sham rats. Data from patch-clamp experiments demonstrate that the total Kv current, especially I(A), was dramatically decreased in medium-sized IB4-negative muscle afferent neurons (a subpopulation containing mostly Aδ neurons) from CHF rats compared with 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 1 wk 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 plays a critical role in mediating the exaggerated EPR and muscle afferent sensitization in CHF. NEW & NOTEWORTHY The primary finding of this manuscript is that voltage-gated potassium (Kv) channel dysfunction in DRGs plays a critical role in mediating the exaggerated EPR and muscle afferent sensitization in chronic heart failure (CHF). We propose that manipulation of Kv channels in DRG neurons could be considered as a potential new approach to reduce the exaggerated sympathoexcitation and to improve exercise intolerance in CHF, which can ultimately facilitate an improved quality of life and reduce mortality.
- Published
- 2021