Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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primary integration of baroreceptors reflex [ 82 ], increases density of oxytocinergic

projections to the NTS/DMV area and the local synaptic release of oxytocin [ 7 , 15 ],

thus facilitating the vagal outflow and the appearance of resting bradycardia [ 7 , 80 ]

as well as the slowdown of the heart of trained rats during submaximal exercise

[ 83 ]. These effects were abolished by sinoaortic denervation or oxytocin receptor

blockage in the NTS [ 84 – 86 ]. Taken together, these data demonstrate that increased

pressure during repeated daily exercise sessions activates baroreceptors and the

supramedullary modulatory oxytocinergic pathway that increases the parasympa-

thetic control of the heart.

Together with this effect, data from our laboratory also showed marked reduction

of sympathetic vasomotor activity in the trained SHR, a response completely

blocked by sinoaortic denervation [ 85 ]. Knowing that the generation of sympathetic

activity involves the activation of excitatory glutamatergic neurons in autonomic

areas and that oxidative stress and inflammation are potent activators of neuronal

discharge [ 41 – 46 , 50 , 87 ], next we evaluate the effects of exercise training on the

availability of reactive oxygen species and pro-inflammatory cytokines within the

PVN. We observed in the trained SHR a prompt (2 weeks) and marked reduction in

the expression of different NADPH oxidase subunits, normalization of the oxidative

stress, decrease of p42/44 MAPK phosphorylation and NF-kB transcriptional activ-

ity, with a great reduction of interleukin-6 (IL-6) and tumor necrosis factor-alpha

(TNFα) expression in the PVN [ 3 ]. These responses were accompanied by decreased

neuronal activity within this area as documented by Stern et al. [ 88 ]. Again, trained-

induced changes in the PVN occurred simultaneously with normalization of barore-

ceptor reflex control of heart rate and preceded the appearance of resting bradycardia

and pressure fall [ 3 ]. Training-induced blockade of oxidative stress, attenuation of

the inflammatory profile accompanied by reduction of sympathetic nerve activity

and a partial blood pressure fall are also observed in other autonomic areas, such as

the RVLM [ 46 , 89 ].

Besides the direct effect on pro-inflammatory cytokines expression, aerobic

exercise training is also able to normalize high mobility group box protein 1

(HMGB1) availability in the PVN of the trained SHR. HMGB1, a damage- associated

molecular pattern, acts through toll-like receptor 4 (TLR4) or CXCR4, a chemokine

receptor type 4 in microglial cells, promoting pro-inflammatory cytokines expres-

sion and autonomic dysfunction [ 66 ]. Interestingly, 2-weeks of exercise training

reduces the expression of both HMGB1 and CXCR4, normalizes the elevated trans-

location of NF-kB to the nucleus, restores the activated microglia to the inactive

state, normalizes protein expression of TNFα and IL-6 in the PVN of the SHR,

reduces pressure variability and corrects the autonomic dysfunction without any

change in pressure levels [ 66 ].

Since the most important factor to avoid end-organ damage and mortality in

hypertensive individuals is the reduction of pressure variability, the above- mentioned

findings revealing a close relationship between training-induced cellular/molecular

mechanisms and autonomic benefits show that training is able to interrupt the del-

eterious positive feedback between hyperactive brain RAS, oxidative stress and

16 Experimental Evidences Supporting Training-Induced Benefits in Spontaneously...