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glutamatergic second order neurons activate caudal ventrolateral medulla’s (CVLM)
neurons, which are gabaergic and inhibit the sympathetic premotor neurons within
the rostral ventrolateral medulla (RVLM). These neuronal connections activate
parasympathetic preganglionic neurons and restrain sympathetic outflow to produce
acute cardiovascular adjustments as cardiac output reduction, peripheral vasodila-
tion and decrease in circulating catecholamines, renin and vasopressin, which con-
tribute to reduce and stabilize arterial pressure. On the other hand, during blood
pressure reduction, baroreceptors’ depolarization is attenuated and, consequently,
NTS stimulation. Then, parasympathetic pre-ganglionic neurons of the NA and
DMV are not activated, as well as the sympathetic premotor neurons of the RVLM
(which received continuous stimulation from higher integrative centers) are not
inhibited. Therefore, the arterial pressure fall reflexly leads to unload of parasympa-
thetic and increase of sympathetic activity to bring pressure back to control levels.
It is also known that brainstem integrative autonomic areas are continuously modu-
lated by hypothalamic neuronal circuitries within the paraventricular nucleus (PVN)
and other supramedullary pathways [ 5 , 7 , 11 ]. Vasopressinergic and oxytocinergic
projections from the PVN to the NTS/DMV area are shown to decrease and increase
baroreflex sensitivity, respectively [ 12 – 16 ].
Baroreflex sensitivity is attenuated in both pre-hypertensive and hypertensiveanimals [ 17 , 18 ]. In other words, the magnitude of cardiovascular adjustments, as
changes in heart rate and peripheral vascular resistance, evoked by arterial pressure
oscillations are depressed. Stiffening of the arterial wall, oxidative stress and inflam-
mation in autonomic areas are the main mechanisms that generate baroreflex dys-
function [ 6 , 8 , 19 , 20 ]. As described in the following sections, hypertensive subjects
exhibit several morphological alterations in the wall of arteries resulting in a stiff
vascular wall. As a direct consequence, each pressure wave reduces its mechanical
deformation leading to an attenuated activation of NTS’ second order neurons,
reduced reflex responses to load/unload of baroreceptors and elevated pressure vari-
ability [ 21 , 22 ]. The increased pressure variability augments hydrostatic pressure
oscillations in the capillaries, exposing tissues to short periods of hypoxia and
hyperoxia. These repetitive ischemia-reperfusion episodes activate local renin-
angiotensin system, increase reactive oxygen species availability and pro-
inflammatory cytokines production facilitating the development of end-organ
injuries in several tissues [ 20 , 23 – 26 ]. In addition to increased pressure variability,
autonomic dysfunction promotes end-organ damage through elevated adrenergic
signaling. Beta-adrenergic signaling in the myocardium induces cardiac hypertro-
phy, augments matrix metalloproteinase-2 activity and enhances TGF-β expression
and collagen I and III synthesis. Increased cardiac sympathetic signaling has been
shown to intensify reactive oxygen species production and infiltration of hemato-
poietic mononuclear cells [ 27 – 29 ]. Adrenergic hyperactivation also modifies renin
secretion and sodium/water reabsorption determining abnormal renal function [ 30 ].
Indirectly, renal adrenergic signaling elevates renin release and, consequently,
increases plasma angiotensin II, which, as described subsequently, promotes several
tissue injuries through activated oxidative stress and inflammation.
16 Experimental Evidences Supporting Training-Induced Benefits inflSpontaneously...