Abstract
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.
Highlights
A hallmark of patients suffering from chronic heart failure (CHF) is sympatho-excitation and exercise intolerance [1,2,3,4]
myocardial infarction (MI)-induced cardiac dilation in CHF + anti-brain-derived neurotrophic factor (BDNF) and CHF + vehicle rats was indicated by increased left ventricle (LV) systolic and diastolic diameters and volumes measured by echocardiography at the 6th week post MI
Hemodynamic data collected at the time of the terminal experiments (~10 weeks) further demonstrated that there was a significant increase in left ventricle end-diastolic pressure (LVEDP) in CHF rats compared to sham rats
Summary
A hallmark of patients suffering from chronic heart failure (CHF) is sympatho-excitation and exercise intolerance [1,2,3,4]. The cardiovascular system is regulated, in part, by the EPR, a peripheral neural reflex originating in skeletal muscle. Evidence from human and animal studies has demonstrated that increases in heart rate, arterial pressure and ventilation in response to activation of this reflex are enhanced in CHF patients and animals [11,12,13,14,15]. Experimental and clinical studies by us [16] and others [11,12,13,14,15] have provided convincing evidence that the enhanced mechanically sensitive afferent input of this reflex (i.e., mechanoreflex) contributes to the exaggerated EPR in CHF while the metaboreflex is blunted. Further molecular mechanisms underlying the selective sensitization of the mechano-sensitive afferent limb in CHF has not been fully explored
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