Time-Dependent Effects of Training on Cardiovascular Control in Spontaneously Hypertensive Rats: Role for Brain Oxidative Stress and Inflammation and Baroreflex Sensitivity

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.

Downregulation of the Vascular Renin-Angiotensin System by Aerobic Training – Focus on the Balance Between Vasoconstrictor and Vasodilator Axes –

“…The His-Leu peptide released was measured by fluorimetry (360 nm of expression, NADPH oxidase activity, reactive oxygen species formation, NF-kB translocation to the nucleus and pro-inflammatory cytokines expression, which were positively correlated with improvement of cardiovascular function and blood pressure fall. 13, 14 Interestingly, the effects of training on brain RAS expression were similar to those observed in hypertensive rats after chronic AT1 receptor blockade, 15 suggesting the potentiality for aerobic training to block RAS hyperactivity. Previous studies in heart failure and hypertensive animals also indicated that training reduced the overactivity of the vasoconstrictor arm while preserving the RAS vasodilator axis in the heart, kidney, skeletal muscle and aorta.…”

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

“…This major pathological feature in hypertension is closely related to endorgan injuries, as retinopathy, glomerular sclerosis, stroke, and myocardial infarction (25,42). Experimental studies from our group have shown that hypertensive rats had increased proinflammatory cytokines expression in autonomic control areas, such as the hypothalamic paraventricular nucleus (PVN) (2,31). In addition, it was demonstrated that acute microinjection of proinflammatory molecules into the PVN of normotensive rats causes elevation of both arterial pressure and renal sympathetic nerve activity (38).…”

Resistance training and cardiovascular autonomic modulation in humans: a systematic review and meta-analysis

“…The benefits of exercise training in CAM could be due to many factors, including increased neuronal activity or plasticity in the cardiovascular control center, increased central arterial compliance that improves baroreflex sensitivity, reduced angiotensin II and renin, decreased catecholamine levels, decreased beta-adrenergic receptor density or improved endothelial function and oxide nitric availability with exercise training (11,12,37,38) . Whether endurance training prompt different effects compared to RT, it is quite difficult to identify among all the causes of these adaptations, the ones that should not happen following RT.…”

“…Whether endurance training prompt different effects compared to RT, it is quite difficult to identify among all the causes of these adaptations, the ones that should not happen following RT. However, the increase in central arterial stiffness following RT (39) , might explain at least part of the divergent results between exercise training types, since it reduces baroreflex sensitivity (11) . Since nervous system is complex and interact with the other systems we guess several mechanisms related to HRV and exercise stills unknown.…”

“…In fact, beneficial impacts of endurance-training on HRV have been seeing in diverse health conditions, ages and physical condition basal level (10) . The benefits in HRV through exercise training could be due to many factors including higher neuronal activity, improved baroreflex sensitivity, increase in vasoactive factors concentration and improvements in endothelial function (11,12) . Otherwise, the resistance training (RT) effects on HRV are quite controversial.…”