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trials designed to evaluate the antihypertensive efficacy of unilateral carotid body
resection in resistant hypertensive patients [ 31 ]. However, the mechanism triggering
sustained chemoreflex activation, especially in obesity hypertension, has remained
elusive. Recent experimental evidence in a model of obesity-induced hypertension
by administration of a high-fat diet provides support to the hypothesis that hypox-
emia drives carotid body activation in obesity hypertension, with attendant sympa-
thoexcitation. This canine model shares many of the metabolic, neurohumoral, and
hemodynamic characteristics of human obesity hypertension [ 4 , 15 ]. Furthermore,
obesity is commonly characterized by high metabolic rate and oxygen consumption
along with impaired ventilatory mechanics which may lead to chronic hypoxemia.
Indeed, dogs fed with a high-fat diet for 4 weeks were hypoxemic, tachypneic, but
eucapnic. Moreover, denervation of the carotid body by stripping the carotid sinus
area resulted in a marked attenuation of obesity hypertension [ 31 ]. These data sup-
port the notion that in obesity hypertension, chronic hypoxemia provides the tonic
drive for peripheral chemoreflex activation which results in sustained sympathoex-
citation and hypertension.
Obstructive sleep apnea (OSA), common in obese and resistant hypertensive
patients, has long been heralded as the major, if not the exclusive, cause of sympa-
thetic activation in obesity. Obese hypertensive patients with OSA have sustained
sympathetic activation beyond episodic occurrences during the nighttime. Although
no mechanism has been proposed to explain this transition from acute to chronic
and sustained sympathetic activation [ 24 ], the study in obese dogs [ 31 ] provides
support for the concept that chronic intermittent hypoxemia (which is not routinely
evaluated in clinical studies) may provide the tonic excitatory drive for chemoreflex
activation resulting in sympathoexcitation in patients with OSA [ 32 ].
Several behavioral factors have been proposed to explain sympathetic activation
in obesity-related hypertension, including overfeeding, sedentary lifestyle, or
chronic mental stress [ 12 ]. Additionally, a plethora of experimental evidence sug-
gested the role of humoral factors in mediated sympathoexcitation in hypertension,
associated or not with obesity. These include hyperinsulinemia and associated insu-
lin resistance, nitric oxide deficiency, endothelins, vasopressin natriuretic peptides,
the renin-angiotensin system, and cytokines released from adipocytes such as tumor
necrosis factor-α and interleukin-6 or leptin [ 9 , 12 , 24 , 33 ]. While the role of leptin
as a link between obesity, sympathoexcitation, and hypertension has been exten-
sively documented in experimental studies in rodents [ 33 ], the data in humans is
still scarce owing to methodological limitations [ 5 ]. Furthermore, although insulin-
induced sympathoexcitation has been documented in human studies, the role of
hyperinsulinemia in mediating obesity-hypertension has been questioned because
insulin fails to increase blood pressure in humans and dogs [ 34 ]. Activation of the
renin-angiotensin system may promote sympathetic nervous system activation by
actions at the central nervous system level and peripheral nerve terminals. This
notion is strongly supported by accumulating clinical data indicating that both
angiotensin converting enzyme inhibitors and angiotensin II receptor blockers
reduce central sympathetic outflow in hypertensive individuals [ 18 ]. However, due
to the pleiotropic beneficial effects of these agents, especially upon comorbidities in
R. Iliescu and D.N. Şerban