Exercise training increases GAD65 expression, restores the depressed GABAA receptor function within the PVN and reduces sympathetic modulation in hypertension.

GABAergic inhibitory input within the paraventricular hypothalamic nucleus (PVN) plays a key role in restraining sympathetic outflow. Although experimental evidence has shown depressed GABAA receptor function plus sympathoexcitation in hypertension and augmented GABA levels with reduced sympathetic activity after exercise training (T), the mechanisms underlying T-induced effects remain unclear. Here we investigated in T and sedentary (S) SHR and WKY: (1) time-course changes of hemodynamic parameters and PVN glutamic acid decarboxylase (GAD) isoforms' expression; (2) arterial pressure (AP) and heart rate (HR) responses, sympathetic/parasympathetic modulation of heart and vessels and baroreflex sensitivity to GABAA receptor blockade within the PVN. SHR-S versus WKY-S exhibited higher AP and HR, increased sympathetic reduced parasympathetic modulation, smaller baroreflex sensitivity, and reduced PVN GAD65 immunoreactivity. SHR-T and WKY-T showed prompt maintained increase (2-8 weeks) in GAD65 expression (responsible for GABA vesicular pool synthesis), which occurred simultaneously with HR reduction in SHR-T and preceded MAP fall in SHR-T and resting bradycardia in WKY-T. There was no change in GAD67 expression (mainly involved with GABA metabolic pool). Resting HR in both groups and basal MAP in SHR were negatively correlated with PVN GAD65 expression. Normalized baroreflex sensitivity and autonomic control observed only in SHR-T were due to recovery of GABAA receptor function into the PVN since bicuculline administration abolished these effects. Data indicated that training augments in both groups the expression/activity of GABAergic neurotransmission within presympathetic PVN neurons and restores GABAA receptors' function specifically in the SHR, therefore strengthening GABAergic modulation of sympathetic outflow in hypertension.

Exercise training abrogates age-dependent loss of hypothalamic oxytocinergic circuitry and maintains high parasympathetic activity.

Neuroanatomical studies associating neuronal tract tracing and immunohistochemistry identified reciprocal (ascending noradrenergic/descending oxytocinergic, OTergic) connections between brainstem cardiovascular nuclei and the paraventricular hypothalamic nucleus (PVN). Previous functional studies indicated that exercise training (T) augmented the expression/activity of OTergic pathway and improve the autonomic control of the heart. Knowing that ageing is associated with autonomic dysfunction and sinoaortic denervation blocked T-induced beneficial effects, we hypothesized that T was able to reduce age-dependent impairment by improving the afferent signaling to PVN and augmenting OTergic modulation of cardiovascular control. We evaluated the combined effects of T and age on plastic remodeling of ascending dopamine ß-hydroxylase (DBH+) and descending OT+ pathways and correlated them with cardiovascular parameters. Male Wistar rats were submitted to T or kept sedentary for 8 weeks. After evaluating arterial pressure, heart rate (HR), their variabilities and spectral components in conscious rats at rest, brains were harvested to analyze the plastic remodeling of brain autonomic nuclei (immunofluorescence + confocal microscopy). The density of DBH+ neurons within the nucleus of solitary tract (NTS) and caudal ventrolateral medulla, the number of DBH+ terminals overlapping OT+ neurons in PVN preautonomic nuclei, as well as the density of OT+ neurons and their projections to NTS and dorsal motor nucleus of the vagus were markedly reduced in S rats during 8-weeks of inactivity In contrast, these effects were completely blocked by T and reversed to a large augmentation of DBH+ and OT+ densities in both cell bodies and terminals within autonomic nuclei and target areas. All plastic changes observed correlated positively with parasympathetic activity to the heart (HF-PI, but not with LF-PI) and negatively with resting HR. Data indicate that T, by increasing beneficial neuroplastic adaptive changes within brainstem-PVN reciprocal network, abrogates age-dependent deleterious remodeling and augments parasympathetic modulation of the heart, therefore improving autonomic function. This article is protected by copyright. All rights reserved.

Maintenance of Blood-Brain Barrier Integrity in Hypertension: A Novel Benefit of Exercise Training for Autonomic Control.

The blood-brain barrier (BBB) is a complex multicellular structure acting as selective barrier controlling the transport of substances between these compartments. Accumulating evidence has shown that chronic hypertension is accompanied by BBB dysfunction, deficient local perfusion and plasma angiotensin II (Ang II) access into the parenchyma of brain areas related to autonomic circulatory control. Knowing that spontaneously hypertensive rats (SHR) exhibit deficient autonomic control and brain Ang II hyperactivity and that exercise training is highly effective in correcting both, we hypothesized that training, by reducing Ang II content, could improve BBB function within autonomic brain areas of the SHR. After confirming the absence of BBB lesion in the pre-hypertensive SHR, but marked fluorescein isothiocyanate dextran (FITC, 10 kD) leakage into the brain parenchyma of the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract, and rostral ventrolateral medulla during the established phase of hypertension, adult SHR, and age-matched WKY were submitted to a treadmill training (T) or kept sedentary (S) for 8 weeks. The robust FITC leakage within autonomic areas of the SHR-S was largely reduced and almost normalized since the 2nd week of training (T2). BBB leakage reduction occurred simultaneously and showed strong correlations with both decreased LF/HF ratio to the heart and reduced vasomotor sympathetic activity (power spectral analysis), these effects preceding the appearance of resting bradycardia (T4) and partial pressure fall (T8). In other groups of SHR-T simultaneously infused with icv Ang II or saline (osmotic mini-pumps connected to a lateral ventricle cannula) we proved that decreased local availability of this peptide and reduced microglia activation (IBA1 staining) are crucial mechanisms conditioning the restoration of BBB integrity. Our data also revealed that Ang II-induced BBB lesion was faster within the PVN (T2), suggesting the prominent role of this nucleus in driven hypertension-induced deficits. These original set of data suggest that reduced local Ang II content (and decreased activation of its downstream pathways) is an essential and early-activated mechanism to maintain BBB integrity in trained SHR and uncovers a novel beneficial effect of exercise training to improve autonomic control even in the presence of hypertension.

Downregulation of the vascular renin-angiotensin system by aerobic training - focus on the balance between vasoconstrictor and vasodilator axes - .

BACKGROUND: Hyperactivity of the renin-angiotensin system (RAS) and functional deficits in hypertension are reduced after exercise training. We evaluate in arteries, kidney and plasma of hypertensive rats the sequential effects of training on vascular angiotensinogen, Ang II and Ang (1-7) content. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were trained or kept sedentary (S) for 3 months. After hemodynamic measurements (weeks 0, 1, 2, 4, 8 and 12), blood, arteries and kidneys were obtained to quantify the angiotensin content (HPLC) and angiotensinogen expression (Western Blotting). SHR-S vs. WKY-S exhibited elevated pressure, increased angiotensinogen and angiotensins' content in the renal artery with a high Ang II/Ang (1-7) ratio (~5-fold higher than in the femoral artery, kidney and plasma, and 14-fold higher than in the aorta). Training promptly reduced angiotensinogen expression and downregulated the RAS in the renal SHR artery (1st-12th week), with a specific reduction of the vasoconstrictor axis; significant reduction of the AngII/Ang (1-7) ratio (36%, T4-T8) occurred simultaneously with significant pressure fall (5%). In other SHR arteries, plasma and kidneys and in all WKY tissues, T-induced AngII and Ang (1-7) reductions were proportional, maintaining the AngII/Ang (1-7) ratio. CONCLUSIONS: Vascular RAS is not equally expressed in vessels, having crucial importance in the renal artery. In the renal SHR artery, training downregulates the vasoconstrictor and preserves the vasodilator axis while in other tissues and plasma training reduces both RAS axes, thus maintaining the vasoconstriction/vasodilatation balance in a lower level.