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Peripheral chemoreflex, one of the most important regulatory mechanisms forrespiratory responses [ 31 ], is also crucial for the regulation of autonomic control.
Chemoreceptors are located bilaterally in the carotid body, at the bifurcation of
common carotid artery. Within the carotid body chemosensitive type I cells are
responsible for the transduction of PO2 (most important), PCO2 and pH levels in
action potentials’ frequency. Acute reduction of PO2 increases AMP/ATP ratio
leading to AMP-activated protein kinase (AMPK) activation, which inhibits oxygen-
sensitivity potassium channels inducing the chemoreceptor depolarization [ 32 ]. The
hypoxic environment also attenuates nitric oxide and carbon monoxide production
and intensifies reactive oxygen species formation, which promotes further type 1
cell depolarization [ 33 , 34 ]. From the carotid body’s cells, afferents fibers stimulate
chemosensitive second order neurons located in the NTS, which project and activate
rostral ventrolateral medulla sympathetic pre-motor neurons [ 35 ] producing reflex
cardiovascular adjustment to hypoxia, as the elevation of peripheral vascular resis-
tance, cardiac contractility, cardiac output and arterial pressure.
Chemoreflex dysfunction in hypertension was described since early 80’s in SHRs[ 36 ]. In the last years, the role of chronic chemoreceptor activation in the establish-
ment and maintenance of autonomic dysfunction and elevated arterial pressure was
demonstrated in experimental studies. Juvenile SHRs in the pre-hypertensive phase
already exhibit hyperactivity of carotid body cells [ 37 – 39 ]. Interesting, selective
denervation of the carotid bodies in SHRs decreases both sympathetic activity and
arterial pressure [ 37 , 40 ].
2.1 Brain Cellular/Molecular Mechanisms Generating
Autonomic Dysfunction
Besides the previously mentioned vascular abnormalities, hyperactivity of the
renin-angiotensin system, increased availability of reactive oxygen species and pro-
inflammatory cytokines were described in the brain of hypertensive individuals. In
angiotensin II-induced hypertension, angiotensinergic and inflammatory signaling
are shown to increase NADPH oxidase activation, superoxide anion release and
neuronal calcium influx in circumventricular areas as the subfornical organ. Since
the subfornical neurons project and activate sympathetic pre-motor neurons located
in the PVN, increased neuronal activity in the subfornical organ leads to baroreflex
dysfunction, increased sympathetic outflow and elevated blood pressure [ 41 – 45 ]. In
several models of hypertension, such as the SHR [ 2 , 3 , 46 ], angiotensin II-induced
[ 44 , 47 – 51 ], renovascular [ 52 – 54 ] and high salt diet hypertension [ 55 ], in addition
to areas outside the blood-brain barrier, angiotensinergic, oxidative and inflamma-
tory signaling were also observed in autonomic brain areas inside the blood brain
barrier as the PVN, RVLM and NTS.
G.S. Masson and L.C. Michelini