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.

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Exercise training prevents the exaggerated exercise pressor reflex in rats with chronic heart failure

Journal of Applied Physiology ◽

10.1152/japplphysiol.01273.2009 ◽

2010 ◽

Vol 108 (5) ◽

pp. 1365-1375 ◽

Cited By ~ 34

Author(s):

Han-Jun Wang ◽

Yan-Xia Pan ◽

Wei-Zhong Wang ◽

Lie Gao ◽

Matthew C. Zimmerman ◽

...

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Chronic Heart Failure ◽

Exercise Training ◽

Exercise Intolerance ◽

Cardiovascular Reflexes ◽

Exercise Pressor Reflex ◽

Static Contraction ◽

Pressor Reflex ◽

Passive Stretch

An exaggerated exercise pressor reflex (EPR) occurs in the chronic heart failure (CHF) state, which contributes to exercise intolerance and excessive sympathoexcitation during exercise. Exercise training (ExT) improves abnormal cardiovascular reflexes in CHF. Whether ExT can normalize the exaggerated EPR function remains to be determined. This study was designed to investigate the effects of ExT on the EPR and on the mechanical or metabolic components of this reflex in sham-operated and CHF rats. The EPR was activated by static contraction induced by electrical stimulation of L4/L5 ventral roots. The afferent fibers associated with the mechanoreflex and metaboreflex were activated by passive stretch and hindlimb arterial injection of capsaicin (0.1 and 1 μg/kg, 0.2 ml), respectively. Heart rate, blood pressure, and sympathoexcitatory responses during the activation of these reflexes were compared in sham + sedentary (Sed), sham + ExT, CHF + Sed, and CHF + ExT rats. Compared with sham + Sed rats, CHF + Sed rats exhibited exaggerated heart rate and pressor and sympathoexcitatory responses to either static contraction or passive stretch, whereas the cardiovascular responses to injection of capsaicin were blunted. Eight to ten weeks of ExT normalized the exaggerated responses induced by static contraction or passive stretch and partially improved the blunted responses due to intra-arterial capsaicin in CHF rats. ExT had no significant effect on the EPR and mechanoreflex and metaboreflex functions in sham rats. These findings suggest a potential therapeutic role for ExT in minimizing arterial pressure and sympathetic outflow following activation of the EPR in the CHF state.

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Exercise training improves the exercise pressor reflex dysfunction via ameliorating the skeletal muscle oxidative stress in chronic heart failure

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.952.8 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Han‐Jun Wang ◽

Yan‐Xia Pan ◽

Wei‐Zhong Wang ◽

Irving H. Zucker ◽

Wei Wang

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Exercise Training ◽

Exercise Pressor Reflex ◽

Pressor Reflex

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p22phox inhibition in Skeletal Muscle Normalizes the Exaggerated Exercise Pressor Reflex in Chronic Heart Failure

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.619.1 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Hanjun Wang ◽

Lie Gao ◽

Matthew C. Zimmerman ◽

Irving H. Zucker ◽

Wei Wang

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Chronic Heart Failure ◽

Exercise Pressor Reflex ◽

Pressor Reflex

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Downregulated Kv4.3 expression in the RVLM as a potential mechanism for sympathoexcitation in rats with chronic heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00145.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. H945-H955 ◽

Cited By ~ 42

Author(s):

Lie Gao ◽

Yulong Li ◽

Harold D. Schultz ◽

Wei-Zhong Wang ◽

Wei Wang ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Mrna Expression ◽

Cell Line ◽

P38 Mapk ◽

Critical Role ◽

Mapk Signaling ◽

Neuronal Membrane ◽

Ang Ii ◽

Voltage Gated

Elevated central angiotensin II (ANG II) plays a critical role in the sympathoexcitation of chronic heart failure (CHF) by stimulating upregulated ANG II type 1 receptors (AT1R) in the rostral ventrolateral medulla (RVLM). However, the link between enhanced ANG II signaling and alterations in the electrophysiological characteristics of neurons in the RVLM remains unclear. In the present experiments, we screened for potentially altered genes in the medulla of rats with CHF that are directly related to neuronal membrane conductance using the Rat Genome 230 2.0 Array GeneChip. We found that CHF rats exhibited a 2.1-fold reduction in Kv4.3 gene expression, one of the main voltage-gated K+ channels, in the medulla. Real-time RT-PCR and Western blot analysis confirmed the downregulation of Kv4.3 in the RVLM of CHF rats. In intact animals, we found that microinjection of the voltage-gated potassium channel blocker, 4-aminopyridine, into the RVLM evoked a sympathoexcitation and hypertension in both normal and CHF rats. CHF rats exhibited smaller responses to 4-aminopyridine than did normal rats. Finally, we used a neuronal cell line (CATH.a neurons) to explore the effect of ANG II on Kv4.3 expression and function. We found that ANG II treatment significantly downregulated mRNA and protein expression of Kv4.3 and decreased the A-type K+ current. Employing this cell line, we also found that the ANG II-induced inhibition of Kv4.3 mRNA expression was attenuated by the superoxide scavenger Tempol and the p38 MAPK inhibitor SB-203580. The effects of ANG II were abolished by the AT1R antagonist losartan. We conclude that the sympathoexcitation observed in the CHF state may be due, in part, to an ANG II-induced downregulation of Kv4.3 expression and subsequent decrease in K+ current, thereby increasing the excitability of neurons in the RVLM. The ANG II-induced inhibition of Kv4.3 mRNA expression was mediated by ANG II-AT1R-ROS-p38 MAPK signaling.

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Increased Brain-Derived Neurotrophic Factor in Lumbar Dorsal Root Ganglia Contributes to the Enhanced Exercise Pressor Reflex in Heart Failure

International Journal of Molecular Sciences ◽

10.3390/ijms20061480 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1480 ◽

Cited By ~ 3

Author(s):

Alicia Schiller ◽

Juan Hong ◽

Zhiqiu Xia ◽

Han-Jun Wang

Keyword(s):

Heart Failure ◽

Dorsal Root Ganglia ◽

Neurotrophic Factor ◽

Dorsal Root ◽

Pressor Response ◽

Brain Derived Neurotrophic Factor ◽

Current Injection ◽

Exercise Intolerance ◽

Exercise Pressor Reflex ◽

Pressor Reflex

An exaggerated exercise pressor reflex (EPR) is associated with excessive sympatho-excitation and exercise intolerance in the chronic heart failure (CHF) state. We hypothesized that brain-derived neurotrophic factor (BDNF) causes the exaggerated EPR via sensitizing muscle mechanosensitive afferents in CHF. Increased BDNF expression was observed in lumbar dorsal root ganglia (DRGs) from CHF rats compared to sham rats. Immunofluorescence data showed a greater increase in the number of BDNF-positive neurons in medium and large-sized DRG subpopulations from CHF rats. Patch clamp data showed that incubation with BDNF for 4–6 h, significantly decreased the current threshold-inducing action potential (AP), threshold potential and the number of APs during current injection in Dil-labeled isolectin B4 (IB4)-negative medium-sized DRG neurons (mainly mechano-sensitive) from sham rats. Compared to sham rats, CHF rats exhibited an increased number of APs during current injection in the same DRG subpopulation, which was significantly attenuated by 4-h incubation with anti-BDNF. Finally, chronic epidural delivery of anti-BDNF attenuated the exaggerated pressor response to either static contraction or passive stretch in CHF rats whereas this intervention had no effect on the pressor response to hindlimb arterial injection of capsaicin. These data suggest that increased BDNF in lumbar DRGs contributes to the exaggerated EPR in CHF.

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