p22phox inhibition in Skeletal Muscle Normalizes the Exaggerated Exercise Pressor Reflex in 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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