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Current Vascular Pharmacology, 2014, 12, 16-22
The Pathophysiological Basis of Carotid Baroreceptor Stimulation for the
Treatment of Resistant Hypertension
Dragan Lovic1*, Athanasios J. Manolis2, Branko Lovic1, Vesna Stojanov3, Milan Lovic4, Andreas Pittaras5
and Branko Jakovljevic3
1
Clinic for internal disease InterMedica, Nis, Serbia; 2Asklepeion General Hospital, Athens, Greece; 3 Medical School
University Belgrade, Clinical Center Serbia, Belgrade, Serbia; 4Institute Niska Banja, Nis, Serbia; 5Mediton Medical
Center Cardiology, Athens, Greece
Abstract: The prevalence of resistant hypertension and existing limitations in antihypertensive drug therapy renders the
interventional management of hypertension an attractive alternative. Carotid baroreceptors have been traditionally thought
to be implicated only in short-term blood pressure regulation; however recent evidence suggests that the baroreceptors
might play an important role even in the long-term blood pressure regulation. Electrical baroreflex stimulation appears
safe and effective and might represent a useful adjunct to medical therapy in patients with resistant hypertension. This
review endeavors to summarize the complex pathophysiology of blood pressure regulation, to describe the baroreflex
circuit, its anatomy and physiology, to present previous data refuting a role for the baroreceptors in the long-term control
of blood pressure and recent animal and human data suggesting an effective role of carotid baroreceptor activation in
long-lasting blood pressure reduction. In this paper we attempt to critically evaluate existing information in this area and
provide the scientific basis for carotid baroreceptor stimulation in the management of resistant hypertension.
Keywords: Resistant hypertension, baroreceptors, carotid baroreceptor stimulation.
INTRODUCTION
Arterial hypertension is a multifactorial disease with several factors contributing to the pathogenesis of blood pressure elevation [1]. Hypertension is a major health problem
worldwide, with a large prevalence in general population.
According to World Health Organization data, about 30 50% of the adult population have hypertension. The prevalence of hypertension in 2025 is expected to increase by 60%
(29.2% - 1.56 billion people) compared to 26.4% (972 million people) in year 2000 [2]. In the USA, the prevalence of
hypertension (defined as BP 140/90 mmHg and/or the use
of any antihypertensive drug) was estimated at 33.6%, or
more than 73 million adults [3]. Hypertension is among the
most important independent risk factors for cardiovascular
(CHD) and chronic kidney diseases (CKD). The risk of endstage renal disease and myocardial infarction is four times
higher in persons with systolic blood pressure above 160
mmHg in comparison to persons with normal blood pressure,
and the risk of developing heart failure is two times higher in
individuals over the age of forties [3,4].
blood pressure below target levels of <140/90 mmHg [5].
Recent European data reveal that 38.8% of treated hypertensive patients achieved the blood pressure target of <140/90
mmHg [6]. In some patients with uncontrolled hypertension,
it is difficult to obtain blood pressure goals, despite the use
of combinations of antihypertensive drugs. Resistant hypertension is defined as the inability to achieve blood pressure
goals despite the use of at least three antihypertensive drugs
(including a diuretic) in maximum tolerated doses [7,8]. Resistant hypertension also includes patients whose blood pressure is controlled by the use of four or more antihypertensive
drugs [9].
Although major therapeutic strides in the hypertension
province have been accomplished during the previous century, numerous frustrations still exist in antihypertensive
drug therapy. Epidemiological studies worldwide indicate
that, despite using powerful antihypertensive drugs, less than
30% of all patients with hypertension succeed to keep their
While the exact prevalence of resistant hypertension is
unknown, clinical studies suggest that it is not rare, probably
diagnosed in 20-30% of all patients with hypertension. The
incidence of resistant hypertension increases as the population
becomes older and obese [10]. The estimated prevalence of
resistant hypertension in the ALLHAT, VALUE, CONVINCE
and ASCOTT studies ranged from 7% to 15% [11]. It has to
be noted however that resistant hypertension and uncontrolled
hypertension are two distinct entities, with resistant hypertension representing only a small fraction of uncontrolled hypertension. Uncontrolled hypertension includes patients with
blood pressure levels above goal irrespective of the number
and type of administered antihypertensive drugs. In contrast,
resistant hypertension is restricted in patients taking 3 or more
drugs, one of them being a diuretic.
*Addresss correspondence to this author at the Clinic for internal disease
InterMedica, Hypertension Centre, Jovana Ristica str. 20-2; 18000 Nis,
Mediana, Serbia; E-mails: [email protected]; [email protected]
Patients with resistant hypertension are at higher risk of
cardiovascular morbidity and mortality compared with those
whose hypertension is well controlled [9,10,12]. Increased
cardiovascular risk among patients with resistant hyperten-
1875-6212/14 $58.00+.00
© 2014 Bentham Science Publishers
The Pathophysiological Basis of Carotid Baroreceptor Stimulation
sion depends on blood pressure [4] and the presence of associated co-morbidities, including diabetes mellitus, sleep apnea, obesity, left ventricular hypertrophy and renal disease
[10,12,13].
Given the above, the treatment of patients with resistant
hypertension in the last decade attracts growing attention.
The need for alternative treatment approach has been widely
recognized in recent years. That is why an interventional
treatment of hypertension, which was abandoned after the
mid of the twentieth century, was recently re-invented and
gained intense scientific interest. In this respect, in the treatment of resistant hypertension, a special attention is paid to
carotid baroreceptors stimulation and to sympathetic renal
denervation, which show promising preliminary results
[14,15]. An adequate control of blood pressure reduces cardiovascular risk independent of the class of drugs [16]. Any
therapy that can reduce blood pressure in patients with resistant hypertension may be useful.
HISTORY OF BARORECEPTOR INVESTIGATION
Control of blood pressure by an arterial reflex has been
probably known since ancient times. The observation in Ancient Rome that pressing on the arteries of the neck in animals produced sedation might have been the first notice of
this homeostatic mechanism [17]. A Syrian doctor, Serapion,
used carotid compression for curing headache during the
ninth century [18]. Even in the beginning of the 20th century,
it was well known that blood pressure increases in response
to psychoemotional stimuli. Thus, it was widely held that the
SNS contributed in initiating and maintaining hypertension.
It has been suggested that the activation of the sympathetic
splachnic nerves actually resulted in renal vasoconstriction
and ischemia. Indeed, bilateral supradiaphragmatic splach-
Fig. (1). Physiological view of the baroreceptors function.
Current Vascular Pharmacology, 2014, Vol. 12, No. 1
17
nicectomy has been shown to improve hypertension and target organ damage in the long-term [19].
Since the arterial baroreflex represents a major inhibiting
mechanism of the SNS, it seemed rational to assume that an
alteration in baroreflex activity is implicated in hypertension’s pathogenesis [20]. Indeed, Folkow stated that: “The
reflex control is primarily based on the general inhibition
input from the various sets of stretch receptors” [21], and
“Already early common variants of human primary hypertension, as well as spontaneously hypertensive rats, exhibit
an evidently “primary” central hyper-reactivity to psychosocial stimuli” [22].
CARDIAC
FACTOR
BARORECEPTORS
-
NEUROGENIC
The history of medicine is full of myths, misperceptions,
and misconceptions. The role of arterial baroreflex in blood
pressure control represents such an issue, although the reciprocal relationship between baroreceptor input and sympathetic output has been extensively studied over the years.
The carotid baroreflexes are major sentinels in our homeostatic system of blood pressure control. The carotid sinuses
monitor the blood pressure intra-arterially and then alter accordingly the sympathetic tone, through the vasomotor centers in the central nervous system. Specifically, when the
blood pressure increases, the afferent impulse traffic is increased, and the vasomotor areas reduce the flow of the
sympathetic signals to the periphery, with an end-result of
blood pressure and heart rate reductions; the opposite effect
is observed when blood pressure decreases.
The importance of the carotid sinus in the modulation of
autonomic tone and the regulation of blood pressure has been
long recognized [23,24]. Baroreceptors in conjunction with
18 Current Vascular Pharmacology, 2014, Vol. 12, No. 1
the vasomotor center in the medulla oblongata and vagal
nuclei, are involved in the regulation and maintenance of
normal blood pressure (Fig. 1). Baroreceptors are located in
the aortic arch and carotid sinus. The system of baroreceptors includes vasomotor center and vagal component, programmed to react to any change in blood pressure. Increase
in blood pressure over baroreceptors afferent fibers leads to
activation of inhibitory neurons, and thereby to inhibition of
the vasomotor center and up-regulation of vagal center,
which leads to reduction of blood pressure and decrease in
total peripheral vascular resistance. It also leads to bradycardia due to increased vagal tone and to a decrease of minute
volume and cardiac output. A decrease of blood pressure
through the excitation of neurons leads to activation of the
vasomotor center and vagal inhibition, which results in an
increase in blood pressure due to peripheral vasoconstriction
and in the increase in total peripheral vascular resistance and
cardiac output [1]. Baroreceptors inhibit sympathetic output,
reducing the release of renin and antidiuretic hormone,
which reduce intravascular volume and tone [25]. The stimulation of carotid baroreceptors reduces renal sympathetic
tone, which might contribute to blood pressure reduction
[26].
Disruption of proper functioning of this system is thought
to be among the important factors in the pathogenesis of essential hypertension. It is assumed that a reduced sensitivity
of carotid baroreceptors to normal stimulation, or function at
a higher sensitivity, might lead to the increase and maintenance of high blood pressure [1]. Experimental data support
this hypothesis by showing that when continuously stimulated in arterial hypertension, baroreceptors may fail to lower
blood pressure, which resets at a higher level [27].
THE ARTERIAL BARORECEPTOR AUTONOMIC
REFLEX
Autonomic function occurs mainly through autonomic
reflexes, whereas a variety of factors might influence and
modulate these reflexes. The baroreflex represents a typical
paradigm of autonomic reflexes, involving sensory receptors,
signal transmission and interpretation, motor neurons, and
effector cells.
The exact anatomy and function of the arterial baroreceptor autonomic reflex remain only partially known, despite
extensive research in this field. The role of carotid baroreflex
in blood pressure regulation is complex, multifactorial [28],
and difficult to unveil, since experimental settings are very
demanding and require microtechniques in tiny areas of the
central nervous system. The carotid arterial baroreflex resembles a ‘bus-route’ with several stops and bus changes.
Arterial baroreceptors consist of carotid and extra-carotid
baroreceptors. Carotid baroreceptors are placed in the right
and left carotid sinus, while extra-carotid baroreceptors are
located in the aortic arch, the heart, and the pulmonary vessels [29]. Arterial baroreceptors represent the initial ‘busstop’ of the baroreflex arc, sensing the stretch induced by
circulating blood on the arterial wall. Physiologic transduction of stretch is common to not only many species but to
various organs and tissues as well; distension at visceral
sites, light touch, and hearing represent such functions. Arterial baroreceptors are currently considered to belong in the
Lovic et al.
epithelial sodium channel (ENaC) family, a family of cation
channels [30]. Although it seems strange to meet this cation
family in the baroreflex circuit, we have to take in consideration that this family is involved in mechano-transduction in
several species (light touch in the rat footpad, touch sensation in Caenorhabditis elegans) [31] and other stretch-related
cells, like the osteoblasts [32].
The stretch on vessel wall sensed by arterial baroreceptor
is transmitted to the central nervous system through the glossopharyngeal nerve (IX cranial nerve) from the carotid
baroreceptors and the vagus nerve (X cranial nerve) from
extra-carotid baroreceptors. Signals are transmitted to the
brain medulla at the dorsal area and reach the nucleus tractus
solitarii (NTS). At the same area arrive afferent fibers from
the thoracic and abdominal region [33]; however, the exact
nature as well as the physiological and pathophysiological
significance of these afferent nerves remains to be clarified.
A wealthy of experimental data indicates that NTS is the
‘final receiver’ of afferent baroreceptor signals [34-39]. NTS
is not only an anatomical region but a functional center as
well. Damage of the NTS area in the dorsal medulla is associated by attenuation of the arterial baroreflex, unveiling its
key role in the baroreflex arc [40-42]. Both intra- and extracellular electrophysiological studies demonstrated that neurons in the NTS region receive synaptic inputs that are induced by baroreceptor activation [43-48]. Arriving afferent
signals stimulate the NTS area resulting in release of neurotransmitters, primarily glutamate [49-53] but also a variety of
other neurotransmitters including catecholamines, angiotensin II and nitric oxide [54-61]. Signal transmission seems
to be regulated by another modulating mechanism, the type
of afferent nerves fibers. Existing data suggests that A-type
fibers have lower threshold levels, provide a dynamic reflex
regulation, and modulate predominantly the heart rate, while
C-type fibers have higher threshold levels, provide steadystate reflex responses, and are more involved in blood pressure regulation [62]. However, these data are not conclusive,
and further research is needed in this area.
Signal transmission leaves NTS and arrives at the caudal
ventrolateral medulla (CVLM), a significant functional
‘stop’ for the baroreflex arc. Within this area the signal is
converted and its so far excitatory nature becomes inhibitory
[63-65]. So, the arterial baroreflex represents the essential
‘brake’ for the smooth function of the sympathetic system
and the CVLM region seems to be the ‘converting’ point.
The CVLM area consists of a rostral group of baroreceptorsensitive neurons and a caudal group of baroreceptorindependent neurons. In parallel, CVLM represents the interchange of excitatory signals that travel from the caudal pressor area (CPA) in the pyramidal decussation to the rostral
ventrolateral medulla (RVLM); the physiological role of the
CPA-induced sympatho-excitation and the potential interplay
with the baroreflex remain to be elucidated.
RVLM is the next ‘bus-stop’. Signals from CVLM,
which are now of inhibitory nature, arrive to RVLM at the
bulbospinal level. The bulbospinal area consists of presympathetic sympatho-excitatory neurons. Extensive research
suggests that the baroreflex arc exerts its action by regulating
the sympathetic activity at RVLM, in a manner that activation of baroreceptors inhibits the sympathetic nervous system
The Pathophysiological Basis of Carotid Baroreceptor Stimulation
Current Vascular Pharmacology, 2014, Vol. 12, No. 1
activity [66-73]. Glutamate seems to be the main mediator in
this area as well, while other neurotransmitters have also
been reported to be implicated in signal transmission [7479]. Another component of the baroreflex circuit in this region is thought to be the mu opioid receptors, which have
been found in the RVLM area and originate from the midline
raphe nuclei. Activation of the mu opioid receptors has been
found to impair the sympathetic baroreflex, although the
significance of this pathway remains to be determined. It has
been reported that RVLM is receiving input from a variety of
sources, and an interaction with the baroreflex input has to
be considered. Apart from baroreceptors, the hypothalamus,
cortex, amygdala, medullary raphe, chemoreceptors, somatosympathetic afferents, respiratory afferents, and PaO2 send
signals to the RVLM region [64,65].
In summary, baroreceptors detect changes in stretch of
the arterial wall, the signals are transmitted through sensory
neurons to the central nervous system, signals are then integrated and converted from excitatory to inhibitory and efferent signals are finally transmitted to peripheral tissues to
exert autonomic reflex actions.
CAROTID BARORECEPTOR
DENERVATION
RESETTING
AND
An important role of the carotid baroreflex in the longterm blood pressure regulation has been significantly challenged for decades based on experiments showing baroreceptor resetting on one hand and absence of persistent hypertension following baroreceptor denervation on the other hand.
Early studies of the baroreceptors role in blood pressure
modulation date back in 1950’s. A study by McCubbin in
1956 investigating the baroreceptor of both normotensive
and hypertensive dogs provided early evidence of the firing
threshold and showed that a higher pressure was required to
elicit baroreceptor function in the hypertensive dogs [80].
Baroreceptor resetting at a higher level in hypertension has
been also shown in several experimental studies [81,82] confirming that resetting of carotid baroreceptor occurs within
minutes and might be implicated in the pathogenesis of hypertension since the baroreceptors are no longer capable of
lowering blood pressure in essential hypertesion.
Denervation of either carotid or aortic baroreceptors was
associated with a transient increase in blood pressure which
was not sustained [83-85], suggesting that baroreceptors are
implicated in the short-term but not in the long-term blood
pressure regulation. However, recent experimental studies
with more accurate methodological settings show persistent
elevation of blood pressure during chronic unloading of carotid baroreceptors [86-89], pointing towards the implication
of carotid baroreceptors in the long-term regulation of blood
pressure levels. Human data with carotid baroreceptor denervation are limited and controversial [90-94].
Taken together, older carotid baroreceptor resetting and
denervation studies suggest that the baroreflex is implicated
in the short-term blood pressure regulation with small, if any,
contribution in the long-term regulation of blood pressure
levels. However, newer data challenge this long-standing
point of view and point towards the involvement of the carotid baroreflex in long-lasting blood pressure elevation.
19
What is even more important however, is the effect of carotid baroreceptor stimulation on blood pressure levels.
Warner et al. electrically stimulated the canine carotid
sinus and found an arterial blood pressure reduction that was
frequency-dependent and maintained even over a 90 min
period of continuous stimulation [95]. Later studies in experimental animals have confirmed blood pressure reduction
and found that it was maintained for the one-year study follow-up [96]. Based on these findings in animal studies, carotid nerve stimulation was studied in humans. Carlsten et al.
in 1958 examined humans undergoing head and neck surgery
and confirmed that carotid stimulation did reduce blood
pressure in a frequency-dependent manner [97]. Several
other studies have been performed in the 60’s and verified
the role of carotid nerve stimulation in the treatment of refractory hypertension [98-101]. Peters et al. in 1980 reported
on his experience with a device that matched stimulator frequency to patient heart rate [102], the idea being that heart
rate elevations signaled increases in sympathetic tone that
would need to be answered by greater activation of the
baroreflex, in order to achieve blood pressure control [103].
Patients implanted with this device achieved blood pressure
lowering both at rest and during exercise. Effective blood
pressure lowering was subsequently reported 12 years after
device implantation [102,104].
CURRENT DATA WITH CAROTID BARORECEPTOR STIMULATION
In the past decade, more sophisticated research has developed with the understanding that nonpharmacologic
means of controlling blood pressure may be a realistic and
necessary alternative. The carotid sinus stimulator is a device
called Rheos. It is manufactured by CVRx, Inc (MN, USA)
and consists of an implanted pulse generator with leads that
tunnel subcutaneously and bilaterally attach to the carotid
sinuses. The device requires surgical implantation under
general anesthesia and is fully programmable after implantation to allow adjustment stimulation parameters [105].
Lohmeier et al. in 2004 examined normotensive dogs that
underwent sustained electrical stimulation of their carotid
sinuses over a 7 days period. They found an immediate fall
in the mean arterial pressure (MAP) of 25 mmHg, and over
the full 7 days the dogs sustained a decrease in MAP [106].
Studies in humans have confirmed the efficacy of this
interventional approach, witch was observed in animals.
Schmidli et al. in 2005, reported on five patients who underwent chronic electrical activation of the baroreflex with a
carotid stimulator [107]. The device produced a graded voltage dependent drop in blood pressure – a relationship that
was sustained even with chronic activation of the baroreflex.
Moreover, these patients were concurrently receiving maximal medical therapy including alpha and beta antagonist,
suggesting that baroreflex activation provides incremental
attenuation of sympathetic tone in the setting of oral
antiadrenergic therapy. This theory is supported by experiments conducted by Irwin et al. on anesthezied dogs [108].
Schimidlli found that electrical carotid stimulation and esmolol infusion applied individually produced similar reduction in blood pressure and heart rate, but produced synergistic effect when applied simultaneously [109].
20 Current Vascular Pharmacology, 2014, Vol. 12, No. 1
Acute blood pressure reduction was noted by using the
Rheos device during elective carotid surgery [110]. Several
case reports in patient with resistant hypertension have
shown the clinical utility and long-lasting reductions in
blood pressure with carotid baroreceptor stimulation, setting
the basis for proof-of-concept, properly designed, clinical
trials [111,112]. Studies performed up to now in patients
with resistant hypertension revealed a significant reduction
in both systolic and diastolic blood pressure, which was evident from the beginning of the study and was maintained
thereafter [113-115]. However, more data is needed in order
to verify the efficacy and safety of this interventional approach for the management of patients with resistant hypertension.
Stimulation of carotid baroreceptors is associated with
heart rate variability and heart rate turbulance changes that
are consistent with a decrease of sympathetic activity and an
increase of vagal tone. These changes are correlated with a
significant decrease in blood pressure. Thus, the data suggest
that the modulation of the autonomic nervous system contributes to a better blood pressure control through stimulation
of carotid baroreceptors in severely hypertensive patients
[116].
Lovic et al.
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CONCLUSION
Resistant hypertension affects a significant number of
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such, any novel therapy for blood pressure control deserves
our attention. Therapeutic lifestyle modification and intensive drug therapy for these patients are frequently proven
inadequate, leaving many patients at a dramatically elevated
risk from the cardiovascular complications associated with
uncontrolled hypertension.
The carotid baroreflex represents an essential component
of blood pressure regulation. The activation of the carotid
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device that electrically stimulates carotid baroreceptors. As
premature results are promising, further studies are needed to
clarify the place of carotid baroreceptor stimulation in the
management of patients with resistant hypertension. The
exact clinical indications for this therapeutic modality have
yet to be established, but its potential seems considerable.
The role of electrical activation of the carotid nerves in the
treatment of arterial hypertension is undefined, just as is the
role of this therapeutic approach in other disease states.
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