Abstract
Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (−13%) at the 4th week, and, by reduced vasomotor component of pressure variability (−28%) and decreased mean arterial pressure (−7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.
Highlights
Baroreflex dysfunction, reflecting primarily an impairment in the vagal efferent component of the baroreceptor reflexes, is an important and common characteristic of arterial hypertension, closely related to sympathetic hyperactivity and activation of tissue and plasma renin-angiotensin systems (RAS), increased blood pressure variability, capillary rarefaction and end-organ damage, all of which lead to an increased mortality risk [1,2]
spontaneously hypertensive rats (SHR) submitted to low intensity T exhibited a significant increase in the aerobic capacity at week 4 (11076157 s), with a further increment at week 8 (13526154 s)
SHR-S group showed a significant decrease on treadmill performance during the experimental period (4796159 s at the 8th week)
Summary
Baroreflex dysfunction, reflecting primarily an impairment in the vagal efferent component of the baroreceptor reflexes, is an important and common characteristic of arterial hypertension, closely related to sympathetic hyperactivity and activation of tissue and plasma renin-angiotensin systems (RAS), increased blood pressure variability, capillary rarefaction and end-organ damage, all of which lead to an increased mortality risk [1,2]. Central TNF-a inhibition reduced the expression of angiotensin type 1 receptor (AT1R), NADPH oxidase, TNF-a and IL-1b, increased the expression of neuronal and endothelial nitric oxide synthase, and reduced production of reactive oxygen species (ROS) in the PVN; central TNF-a inhibition simultaneously decreased plasma norepinephrine levels and reduced cardiac dysfunction in heart failure rats [14]. These findings suggest that PICs and oxidative stress modulate autonomic control
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