155renin-angiotensin system. Global sympathetic suppression by electrical activation
of the carotid sinus (baroreflex activation therapy – discussed in detail below) com-
pletely abolished sympathoexcitation and lowered blood pressure further, while
normalizing the activity of the RAS [ 19 ]. Furthermore, suppression of central sym-
pathetic outflow by baroreflex activation has substantial chronic effects to lower
arterial pressure by mechanisms independent of decreasing activation of α1- and
β-adrenergic receptors. Blood pressure lowering in dogs receiving a combination of
prazosin and propranolol in doses that abolished the cardiovascular responses to
administration of α1- and β-adrenergic agonists was associated with activation of
the sympathetic nervous system as reflected by a threefold increase in plasma NE
concentration. Global suppression of sympathetic outflow by baroreflex activation
reduced blood pressure further while returning plasma NE levels to control levels
[ 20 ]. These studies indicate that baroreceptor unloading and attendant activation of
the sympathetic nervous system are sustained responses to antihypertensive therapy
and likely contribute to the difficulty to manage blood pressure in resistant hyper-
tensive patients.
Resistant hypertensive patients are frequently obese, and this comorbidity adds a
constellation of factors which could contribute to the sympathetic overdrive [ 21 ].
However, it is important to note that sympathetic activation in obesity often occurs
in the absence of hypertension [ 5 , 22 ]. A distinct pattern of sympathetic activation
is present in obese hypertensives, as reflected by additional recruitment of fibers
rather than increased firing rates of single fibers, as found in normotensive obese
[ 23 ], suggestive of a particular mechanism of sympathetic activation in obesity
when hypertension is associated. Furthermore, while cardiac sympathetic activity is
only marginally elevated, renal sympathetic activity, although higher than in normo-
tensive lean individuals, is similar in obese patients with or without hypertension
[ 24 ]. Notwithstanding, pharmacological studies indicate that blood pressure of
obese hypertensive humans depends to a greater extent on the renal sympathetic
nervous system activation than in normotensive obese [ 25 , 26 ].
Experimental and clinical studies have provided evidence for the involvement of
several neurohumoral mechanisms in the sympathetic activation of obesity. Reflex
control of sympathetic activity is impaired in obesity hypertension [ 27 ]. Whereas in
lean hypertensive subjects only baroreflex control of heart rate is attenuated, baro-
reflex control of muscle sympathetic nerve activity is also blunted in obese hyper-
tensive subjects [ 28 ]. If baroreceptors do not completely reset in obesity hypertension,
dysfunctional baroreflex control of sympathetic activity may contribute to sustained
sympathoactivation. In addition to the arterial baroreflex, peripheral chemoreflexes
exert a powerful control over central sympathetic outflow such that activation of the
carotid bodies leads to sympathoexcitation and attendant increases in blood pres-
sure. Studies in the spontaneously hypertensive rat [ 29 ] and patients with primary
hypertension [ 30 ] showed exaggerated sympathetic, pressor, and ventilator
responses to chemoreflex activation by hypoxia and reversal of those variables by
chemoreceptor deactivation in hyperoxic conditions. These observations raised the
possibility that tonic chemoreceptor activation may contribute to sympathetically
mediated hypertension and have led to development of current proof-of-concept
10 Secondary Causes: Work-Up and Its Specificities in CKD: Influence of Autonomic...