C H A P T E R 20

Arterial baroreflexes in humans

Istituto di Clinica Medica IV, University of Milan
GIUS EPPE M AN CIA and Centro di Fisiologia Clinica e Ipertensione,
Ospedale Maggiore, Milan, Italy
Department of Internal Medicine, University of Iowa
A A
College of Medicine, Iowa City, Iowa

CHAPTERCONTENTS ciliano, discovered in the dog that the pressor effects

of occlusion of common carotid arteries were not due
Techniques to cerebral ischemia (as hitherto supposed) but de-
Carotid sinus massage pended on the integrity of nervous structures located
Electrical stimulation of carotid sinus nerves
Section or anesthesia of carotid sinus nerves and vagi near the carotid vessels. It continued in the 1920s with
Occlusion of common carotid arteries the great contributions of two German physiologists,
Neck chamber Hering and Koch, who identified these structures in
Vasoactive drugs animals as an afferent branch of the glossopharyngeal
Nonselective techniques nerves, showed their progressive engagement as a
Arterial Baroreceptor Control of Heart Rate
Autonomic mediation function of increasing carotid blood pressure, and de-
Other properties scribed the resulting progressive hypotensive and bra-
Relationship to base-line R-R interval dycardic effects (151,174).The story further continues
Relationship to respiratory cycle with the blossoming of the studies on the arterial
Arterial Baroreceptor Control of Atrioventricular Conduction
and Ventricles baroreflexes that characterized the 1930s and the pe-
Carotid Baroreceptor Control of Blood Pressure riod from the 1950s to the present. The large amount
Carotid Baroreceptor Influence on Cardiac Output and Total of available information on this topic came from these
Peripheral Resistance studies: the fine anatomical appearance and the elec-
Arterial Baroreceptor Control of Regional Circulations
Arterial Baroreceptor Control of Veins
trophysiological features of the baroreceptor afferents,
Set Point of Carotid Baroreflex the nature of their physiological stimuli, the complex-
Aortic Baroreflexes ity of the central integrating processes of the reflexes,
Factors That Modify Arterial Baroreceptor Control of Circulation and the multiplicity and importance of their cardio-
Age vascular effects in both anesthetized and unrestrained
Exercise
Mental stress animals.
Sleep For obvious ethical and technical reasons, studies
Anesthesia on cardiovascular control exerted by arterial barore-
Central blood volume and posture ceptors have been far more limited in humans, and the
Pathological States
Hypertension
information obtained has been more scanty. However,
Heart rate in the past 25 years these reflexes have been found to
Arterial blood pressure play a role of paramount importance in the circulatory
Arterial baroreflexes as cause of essential hypertension regulation of humans, and they may even participate
Heart disease as a primary or secondary factor in a number of
Carotid sinus syndrome
Other pathological conditions cardiovascular diseases. In this chapter we review this
Modification of Arterial Baroreflexes by Drugs information and attempt to define the picture that
P-Adrenergic antagonists emerges from it (also from information available from
Cardiac glycosides animals).
Antihypertensive drugs

TECHNIQUES

ARTERIAL BAROREFLEXES represent a successful chap- Before describing current knowledge on the cardio-
ter in cardiovascular research. This story began in vascular control exerted by the arterial baroreflexes in
1900 when two Italian physiologists, Pagano and Si- humans, we briefly analyze the different techniques
755
756 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111

used to obtain information on this topic. The analysis Surgical denervation of the carotid bifurcation has
is important because the techniques largely determine permitted evaluation of effects of interrupting the
the quantity and the quality of the collected data. carotid baroreceptor activity in anesthetized patients
(13, 93, 238, 266, 338, 349). Similar results have been
Carotid Sinus Massage found in conscious subjects by anesthetizing the ca-
rotid sinus nerves with local anesthetic agents (142,
Reports on the cardiac effects of massaging the 169, 325). Blockade of the vagi in humans with local
carotid sinuses can be traced back for centuries. In anesthetics has been used to study effects of eliminat-
fact, though its mechanisms were not yet understood, ing aortic baroreceptor input (141, 142).
massage was used in primitive medicine to induce There are, however, major limitations in the use of
unconsciousness. Carotid sinus massage (performed nerve blockade or section to determine tonic restraint
by vigorously stroking one carotid sinus) is still used by arterial baroreceptors. 1 ) These procedures inter-
as a clinical tool for stimulating carotid baroreceptors rupt chemoreceptor (72) as well as baroreceptor influ-
and terminating supraventricular tachycardias and an- ences. 2) It is difficult to assess completeness of the
ginal attacks and for the diagnosis of carotid sinus blockade of baroreceptor input. 3) Local anesthesia
syndrome (201). However, the usefulness of this ma- may block cardiopulmonary vagal afferents as well as
neuver in studying reflex cardiovascular control is aortic and carotid baroreceptor afferents. 4 ) Most
limited. The baroreceptor stimulation induced by the importantly the procedure entails risk and major, al-
massage is extremely strong, is not precise or repro- beit transient, side effects (e.g., disphagia, disphonia,
ducible, and bears little relation to the physiological bilateral laryngeal palsy). Thus nerve blockade or
stimulation of the baroreceptors. section does not appear justified in physiological stud-
ies except under well-controlled surgical conditions.
Electrical Stimulation of Carotid Sinus Nerves
Electrical stimulation of human carotid sinus nerves Occlusion of Common Carotid Arteries
was first performed in 1958 by Carlsten et al. (63). Occlusion of the common carotid arteries inhibits
Shortly thereafter the development of implantable carotid baroreceptors and provides information on
and radiofrequency-operated stimulators made it pos- tonic baroreceptor restraint. This method is a major
sible to activate the sinus nerves in conscious subjects tool for assessing carotid baroreceptor function in
(39,243). This method enjoyed some popularity in the anesthetized and conscious animals (170). Its use in
treatment of supraventricular tachycardias (48), hy- humans has been reported by Roddie and Shepherd
pertension (38, 50, 289, 308, 324), and angina pectoris (273), who were able to train subjects to compress
(45,47,125,276);however, it is no longer used clinically their own carotid arteries against the cervical column,
because repeated stimulation becomes unpleasant and thus producing a marked fall in pulsatile and mean
less effective (45, 91). carotid arterial pressure. Carotid sinus hypotension
Although electrical stimulation of the carotid sinus triggered a significant rise in systemic arterial pres-
nerves has advantages over carotid sinus massage (e.g., sure.
the reproducibility of the stimulus), and useful infor- There are obvious limitations to the occlusion
mation has been obtained by this method, it also has method. Unless carotid pressure above the compres-
major limitations. 1 ) It is invasive. 2) It activates the sion point is always measured the variation in the
carotid baroreflex in an artificial way because the baroreceptor stimulus provided by this maneuver is
activation occurs beyond the natural site (i.e., the not quantifiable. Thus comparisons of the reflex func-
receptors) and because all fibers are excited simulta- tion within and among subjects cannot be made easily.
neously, thus eliminating the recruitment of additional In addition carotid chemoreceptors may be stimulated
units that occurs when baroreceptors are activated by a profound drop in carotid pressure (153, 336).
physiologically. 3) The electrical stimulus involves Finally, bilateral carotid occlusion and catheterization
carotid chemoreceptor as well as baroreceptor fibers. of the carotid arteries are mainly of historic interest in
The baroreceptor activation seems to dominate regard to humans because they involve risk.
chemoreceptor influence (150,206,352);however, elec-
trical stimulation of the carotid sinus nerves augments Neck Chamber
ventilation (43), and the cardiovascular effects may
represent the sum or interaction of the opposing influ- The variable-pressure neck chamber is valuable for
ences of chemoreceptor and baroreceptor activation. studying human carotid baroreflexes. The neck cham-
ber originally consisted of a rigid-walled collar that
Section or Anesthesia of Carotid encircled the neck from the shoulders to the lower
Sinus Nerves and Vagi part of the face and the skull (109). The ends of the
collar were sealed with a rubber border. A vacuum
The tonic inhibitory influence of arterial barorecep- cleaner produced negative pressure in the chamber,
tors can be evaluated by techniques that interrupt which increased transmural pressure across the ca-
baroreceptor input. rotid sinuses, thus increasing the vascular diameter

and physiologically stimulating the carotid barorecep-
tors. Stimulus-response curves encompassing a range
of baroreceptor activities above the tonic level were
obtained with graded levels of negative pressure.
Subsequent neck chambers differ from the original
in several respects. One important advance is the
ability to induce positive as well as negative pressures
within the chamber, thus producing decreases as well
as increases in carotid transmural pressure and carotid
baroreceptor activity. In other words the new neck
chambers allow stimulus-response curves to be col-
lected for ranges of baroreceptor activity that are both
below and above the tonic level of baroreceptor activ-
ity.
There are three new types of neck chambers.
Briefly, the chamber described by Thron et al. (321)
is considerably larger than the other neck chambers
and encloses the head as well as the neck. The subject
breathes through a mouthpiece connected to atmos-
phere. The neck chamber described by Ludbrook et
al. (204) is smaller and encloses only the neck. The
induction of positive- or negative-pressure changes is
made possible by a system of double rubber valves
that prevents air leakage from the chamber. The third
type is a simplified neck chamber devised by Eckberg
et al. (100) initially for neck suction but modified to
also sustain positive pressure. This chamber, which
consists of a malleable lead collar that encompasses
the anterior and lateral aspects of the neck, is versatile
and easy to use. For example, one chamber of this
type can be fitted to most subjects, whereas different
sizes of the other types of chambers are necessary to
fit different neck shapes. Another advantage is the
small air volume between the collar and the neck that
allows more rapid alterations in external pressure than
those with the other chambers, easily reaching pres-
sure-time differential (dP/dt) values similar to or
higher than those characterizing the pulse-pressure
waves (226). However, the neck chamber type of Eck-
berg et al. (100) may have a potential drawback.
Because it does not completely encircle or enclose the
neck, the rapid alterations in external pressure may
POSITIVE NEGATIVE
+50
v
04m
-
4
5 -50
internal jugular vein
-
-..
""d
CHAPTER 20: ARTERIAL BAROREFLEXES 757
not act evenly on the carotid sinuses and arteries. The
result could be displacement and deformation of neck
structures that are not entirely dependent on trans-
mural pressure changes across the carotid sinuses.
The use of neck chambers has been evaluated sys-
tematically in recent years. Ludbrook et al. (204) ex-
amined the possibility that positive neck pressure
induces cerebral ischemia through reduction in the
pressure gradient from the arterial to the venous side
of the head. However, venous blood from the brain
showed no reduction in oxygen saturation during neck
pressure, suggesting that there had been no decrease
in cerebral blood flow and thus excluding the possibil-
ity of cerebral ischemia (117).
Two groups of investigators studied the role of ca-
rotid chemoreceptors in responses to negative (100)
and positive (204) neck pressure. Inhibition of arterial
chemoreceptors produced by increasing arterial 0 2
pressure (Poz) above 500 mmHg did not alter re-
sponses to neck suction or pressure (189, 192). Thus
carotid chemoreceptors may not be important in re-
sponses found with neck chambers.
Trzebski et al. (323) have observed that negative
stimuli induced by this neck chamber were accompa-
nied by transient hyperpnea possibly originating from
stimulation of airway receptors.
Information has also been obtained on transmission
features of the externally applied stimuli to the carotid
vessels. Kober and Arndt (172) showed that positive-
and negative-neck pressure changes resulted in reduc-
tion and increase, respectively, in the diameter of the
common carotid arteries, thus validating a posteriori
the premises on which the technique had been devel-
oped. Furthermore positive- and negative-pressure
changes were transmitted with a negligible delay to
the internal jugular vein, i.e., a vessel adjacent to the
carotid artery (94,204).Ludbrook et al. (204) observed
that the transmission of external pressures to the
carotid vessels, though prompt and sustained through-
out the stimulus, was not perfect (Fig. 1). Tissue
pressure immediately outside the carotid sinus wall
was measured through a catheter inserted percuta-
neck chamber
FIG. 1. Simultaneous record of pressure
tissue
changes in 1 subject in neck chamber, in tissue
adjacent to carotid sinus, in internal jugular
vein at level of carotid sinus, and in cervical
esophagus. Time trace, 5-s and 1-s intervals.
Measurements in internal jugular vein were
made to validate tissue-pressuremeasurements.
[From Ludbrook et al. (204).]
esophaguII
758 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111
neously under local anesthesia. The tissue pressures
varied in a virtually perfect linear relationship with
the externally applied pressures, but the transmission
of the external positive pressure and particularly the
negative pressure to the neck tissues was incomplete.
Interestingly the reduction was similar among the
subjects regardless of neck shape and thickness. Lud-
brook et al. (204) thus concluded that there is little
reason for invasively measuring tissue pressure in each
subject and that a sufficiently precise estimation of
the stimuli applied to the carotid sinus areas may be
obtained by reducing the externally applied pressures
for the average pressure losses observed in their sub-
jects (i.e., 14% positive and 36% negative). Ludbrook
et al. (204) measured pressure in the cervical esopha-
gus in search of a noninvasive procedure even more
precise for estimating neck pressure transmission.
Contrary to a previous report (3211, such measurement
cannot be meaningfully used because it does not re-
produce the pressure loss that occurs a t the carotid
sinuses (see Fig. 1).
Stimuli applied to the carotid sinuses by neck suc-
tion were found to be almost perfectly reproducible by
Eckberg (96), who also found excellent reproducibility
of the heart rate effects of the stimuli when tested in
the same subjects a t an interval of 33-60 days. Mancia
et al. (214) found more variability in the heart rate
responses but reported satisfactory reproducibility for
blood pressure responses.
In conclusion, the neck chamber offers many advan-
tages for studying baroreflexes in humans. 1) It allows
selective stimulation or inhibition of carotid barore-
ceptors. 2 ) A considerable range of baroreceptor activ-
ity can be studied. 3 ) Stimuli and reflex effects are
reproducible. 4 ) Stimuli can be delivered rapidly for
study of phasically controlled and rapidly changing
variables such as heart rate. 5 ) It is possible to examine
baroreflex control of vascular resistance and arterial
pressure as well as heart rate. The latter feature is a
major advantage compared with techniques involving
injection of vasoactive drugs that directly alter vas-
cular resistance and arterial pressure.
The neck chamber also has limitations, however. 1)
The technique is difficult to use: collection of the data
is time consuming, and the subjects are aware of
stimuli delivery. Influence of emotional factors must
be carefully avoided. 2) Alterations in blood pressure
induced by carotid baroreceptors modify the activity
of the aortic baroreceptors, thus opposing the primary
effects of the carotid sinus stimuli. Therefore blood
pressure responses obtained with the neck chamber
may reflect not merely the effects of the carotid ba-
roreceptors but also the combination or interaction of
two opposing baroreceptor influences. This may not
be a limitation when heart rate effects are studied,
however, since the short latency of this reflex response
allows evaluation before significant blood pressure
changes have occurred (21, 43). 3) There is no strin-
gent evidence that other receptors in the neck, e.g.,
airway receptors (354), are not affected during rapid
changes in neck chamber pressure.
Vasoactive Drugs
For many years injection of vasopressor agents to
increase arterial blood pressure and reflexly affect the
heart has been used for termination of paroxysmal
supraventricular tachycardias (26). In the 1960s, how-
ever, the bradycardia caused by pressure-induced
baroreceptor activation was used as a quantitative
estimate of the physiological function of the arterial
baroreflex. Angiotensin was the vasopressor agent
used until the discovery of its direct action on the
heart (175) and the nervous system (290) prompted
the use of phenylephrine, which has since remained
the preferred drug. The technique later included mea-
surements of the tachycardic response to reduction in
blood pressure induced by a vasodilator agent (e.g.,
amyl nitrate, trinitroglycerin) to estimate the barore-
flex during physiological deactivation as well as acti-
vation of the baroreceptors.
Two methods have gained popularity in the quan-
titation of the reflex heart rate responses during drug-
induced pressure changes. Smyth et al. (307) and
Bristow et al. (55) found that after an intravenous
injection of a bolus of angiotensin or phenylephrine
(usually 50-150 pg) blood pressure progressively in-
creased to a level of 20-30 mmHg above the base-line
level, during which time the heart (R-R) interval also
lengthened progressively. If each systolic pressure was
plotted versus the R-R interval of the subsequent
cardiac cycle, a linear relationship would result. The
slope of this relationship was an index of the sensitivity
of the arterial baroreflex control of heart rate. A linear
relationship was also found between the progressive
reduction in systolic pressure and the shortening in R-
R interval induced by a bolus of a vasodilator agent
(256).The relationships maintained an optimal linear-
ity even when systolic pressures and R-R interval were
plotted for the same cardiac cycle, and this was found
to be the best approach to adopt whenever base-line
heart rates were greater than 75 beats/min (254).With
the method described by Korner et al. (la), reflex
alterations in R-R interval were assessed when blood
pressure alterations stabilized for 10-15 s immediately
after the progressive increase or reduction in blood
pressure. This method apparently addresses steady-
state heart rate changes in contrast to the technique
of Smyth, Bristow, Sleight, and colleagues a t Oxford
(55, 307), which focuses on dynamic changes in heart
interval during ramp changes in arterial pressure. Al-
though no major discrepancies have arisen in the
results of the two techniques, some differences exist.
For example, the alteration in baroreflex sensitivity
that occurs in hypertension may be more evident with
the ramp technique than with the steady-state
method. Furthermore the steady-state method may be
more sensitive than the ramp method in evaluating

the sympathetic effects on the heart because the sym-
pathetic effects develop more slowly than the vagal
effects (70, 315,343).
There are several advantages of the vasoactive drug
technique. 1) The heart rate responses are neural
because they are absent in denervated hearts (23,167,
193) and are reduced or abolished when the pressure
changes are prevented (330) or the sinoaortic nerves
are cut (112, 180, 244, 331). 2) The stimuli act in the
same direction on all arterial baroreceptors, as would
normally occur physiologically. 3) The technique is
easy to use. 4 ) The subjects are generally unaware of
the stimulus, so there is little chance of emotional
modification of the reflex response.
There are also limitations, however. The most im-
portant is the inability of this technique to measure
baroreflex control of vascular resistance and blood
pressure, which makes it necessary to infer baroreflex
control of vascular resistance and blood pressure from
heart rate changes, a procedure susceptible to error.
Indeed baroreceptor influences have divergent effects
on different cardiovascular areas (5,166,219,248,333).
Furthermore studies with the neck chamber have
shown a limited correlation between heart rate and
blood pressure effects of baroreceptor stimulation and
deactivation (43, 113, 202, 205). These studies also
demonstrate that baroreceptor effects on blood pres-
sure may be independent of those on heart rate, are
not diminished when heart rate is kept constant by
pacing (43, 113) or autonomic blockade (40, log), and
persist when heart rate effects spontaneously disap-
pear (48, 109, 161, 214).
Reflex responses obtained with vasoactive drugs
may have limited reproducibility. A study in which
several phenylephrine injections were repeated in five
individuals a few months apart showed that average
sensitivities differed by 0.3%,9%, 1176, 21%, and 27%
(138). As discussed by Smyth et al. (307), limited
reproducibility may depend on spontaneous variations
in the central influence that modulate baroreflexes
(222) and may therefore be an unavoidable biological
phenomenon. Reproducibility may also depend on the
ability to identify the precise beginning of a drug-
induced change in pressure among spontaneous pres-
sure variations. This may be why the ramp method
was found to be less reproducible than the steady-
state method in conscious rabbits (112).
Reflexes from the cardiopulmonary region may par-
ticipate to a minor extent during injections of vasoac-
tive agents. A rise in systolic pressure activates left
ventricular receptors, although this stimulus is much
less effective than that provided by a rise in ventricular
diastolic pressure (318). Moreover during injection of
amyl nitrate central venous pressure increases (311),
which may excite atrial receptors.
A component in the arterial baroreceptor activation
obtained with this technique may occur because va-
sopressor agents can stimulate the receptors through
contraction of smooth muscle fibers in the arterial
CHAPTER 20: ARTERIAL BAROREFLEXES 759
walls (30, 31, 153). According to Bergel et al. (30, 31)
this may occur with doses of phenylephrine above 100
pg, which in dogs cause pronounced bradycardia with-
out a concomitant increase in the diameter of the
common carotid arteries. However, this may not be an
important influence in the use of vasoactive drugs to
study baroreflexes. In rabbits, baroreflex sensitivity to
an increase in arterial pressure was no greater when
achieved by phenylephrine injection than when it was
obtained by occlusion of the descending aorta (112).
Likewise the baroreflex sensitivity to a reduction in
arterial pressure was no greater when induced by
nitroglycerin than by occlusion of a vena cava. More-
over in human carotid sinuses smooth muscle fibers
are scarce and seemingly unable to induce barorecep-
tor activation when contracted by topical application
of epinephrine or stimulation of the cervical sympa-
thetic trunk (63).
Nonselective Techniques
Several other techniques have been employed to
study arterial baroreflexes, including the Valsalva ma-
neuver (181, 182, 292), lower-body negative pressure
(see chapter on cardiopulmonary baroreflexes by
Mark and Mancia in this Handbook), and head-up
tilting. These techniques are unquestionably useful in
the study of overall reflex control of the circulation in
humans. However, they perturb other reflexes, such as
cardiopulmonary baroreflexes and ventilatory reflexes,
and thus prohibit selective stimulation of arterial
baroreceptors.
ARTERIAL BARORECEPTORCONTROL
OFHEARTRATE
Vasoactive drugs have been used to study the quan-
titative control of heart rate exerted by the arterial
baroreceptors. By injecting phenylephrine and calcu-
lating the data during the ramp phase of baroreceptor
stimulation in normal subjects, Bristow et al. (54)
found an average lengthening in R-R interval of 13
rns/mmHg rise of systolic pressure. Similar or greater
values were found in other ramp-method studies (101,
256, 307) and in calculations obtained during the
steady-state phase of the drug-induced baroreceptor
stimulation (184, 214). The sensitivity of the barore-
ceptor-heart rate reflex when depressor drugs caused
arterial baroreceptor deactivation was also studied in
normal subjects. Average reductions in R-R interval
of about 3-4 ms/mmHg reduction in systolic blood
pressure were obtained with the ramp method (256),
whereas sensitivities of 9 ms/rnmHg or greater were
reported with the steady-state method (184, 214).
These results show that control of heart rate exerted
by arterial baroreceptors is highly effective throughout
physiological alterations in baroreceptor activity. This
control is tonic, and therefore the baroreflex is poised
to either increase or decrease heart rate during spon-
760 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11
taneous fluctuations in arterial pressure in humans.
These conclusions based on studies with vasoactive
drugs relate to the arterial baroreceptor system as a
whole and do not provide information on the relative
contribution of carotid and aortic baroreceptors.
Autonomic Mediation
There is substantial agreement that the bradycardic
response to baroreceptor stimulation in humans is
mediated through vagal cholinergic mechanisms. Pick-
ering et al. (258) and others (101, 303, 311) demon-
strated that the early lengthening of the R-R interval
that accompanied the phenylephrine-induced rise in
arterial pressure was not reduced by P-adrenergic-
blocking doses of propranolol (162) but was abolished
by atropine. Similar observations were made for the
early lengthening of the R-R interval that occurred in
response to stimulation of the carotid baroreceptors
produced by neck suction (96,99).
Reflex cardiac sympathetic responses are slower
than parasympathetic responses (70, 315, 343), and
Ripley et al. (271) found that a reduction in sympa-
thetic tone participates in the sustained bradycardic
effect of baroreceptor stimulation. However, much
evidence indicates that the sustained component of
the baroreceptor-heart rate reflex also has a predom-
inant vagal cholinergic mediation. The bradycardia
that occurred with a baroreceptor stimulation during
a period corresponding to the steady-state of Korner
et al. (184) was unimpaired by propranolol (102, 131,
193) but was abolished by atropine (102,109,131,167,
193, 207, 241, 291, 355). In addition atropine greatly
attenuated bradycardia observed after 1-2 min of elec-
trical stimulation of the carotid sinus nerves (43, 102).
Furthermore atropine abolished the bradycardia in-
duced by baroreceptor stimulation during exercise, a
condition in which there is increased cardiac sympa-
thetic tone (102, 258). Thus failure to detect a sub-
stantial sympathetic component to baroreflex-medi-
ated bradycardia cannot be attributed to low base-line
sympathetic activity. Bradycardia produced by in-
creases in arterial pressure and baroreceptor stimula-
tion in humans seems to be primarily vagal cholinergic.
On the other hand, information on the autonomic
mechanisms mediating the tachycardic response to
deactivation of arterial baroreceptors is somewhat
conflicting. Pickering et al. (258) reported that in most
subjects the early tachycardia observed after admin-
istration of amyl nitrate was unaffected or increased
by propranolol and abolished by atropine. Similar
observations were made by others (193, 207, 236) for
the tachycardic response to baroreceptor deactivation
during the steady-state phase defined by Korner et al.
(184). These results indicated a predominant vagal
mediation for the reflex response. However, Robinson
et al. (272) reported that the increase in heart rate
produced during infusions of nitroglycerin was reduced
by atropine but could only be abolished by combined
administration of atropine and a P-adrenergic blocker.
Goldstein et al. (133) found that the sustained tachy-
cardic response to 1-to 2-min infusion of nitroglycerin
or to tilting was also not completely prevented by
atropine. Bjurstedt et al. (41) showed that during
lower-body suction the peak tachycardia that accom-
panied reduction in arterial blood pressure was dimin-
ished 52%by propranolol; the remaining response was
abolished by atropine. These results suggest the exist-
ence of a dual rather than a single autonomic media-
tion for baroreflex-mediated tachycardia.
Thus both the early and the delayed depressions of
the sinus node that accompany increases in arterial
pressure and baroreceptor activity appear to be exclu-
sively mediated by an increase in the cardioinhibitory
influence of the vagus. The excitation of the sinus
node that accompanies baroreceptor deactivation is
also largely mediated by the vagus. However, an in-
crease of sympathetic cardiac influence may contrib-
ute to the more sustained component of baroreflex-
mediated tachycardia. This may also explain the ef-
fectiveness of P-adrenergic antagonists in reducing the
persistent tachycardia that accompanies the hypoten-
sion induced by treatment with vasodilators in hyper-
tensive patients.
Other Properties
Four properties of the baroreceptor-heart rate reflex
have been examined: 1 ) the latency of reflex response,
2) its relation to cardiac cycle, 3) its adaptation
throughout stimulation, and 4 ) its duration after the
end of stimulation.
The results on the latency of the reflex have not
been entirely consistent. Pickering and Davies (254)
reported lengthening of the R-R interval when phen-
ylephrine was given to normal subjects after an aver-
0.6
*
S.F.
-60 mmHg. 0.58 rec 10.5
0.4
-n
L
0.3
._
n.
I
0.2
0.1
0
1.5 10 0.5 0 (P wave)
Stimulus-(anticipated) P wave interval (iec)
FIG. 2. Effects of carotid baroreceptorstimuli applied at different
times before appearance of P wave on heart (P-P) interval. 0,
Response to each stimulus; 0,averages obtained at 0.2-s intervals.
Baroreceptor stimuli induced by neck suction of 60 mmHg for 0.58-
s duration. Data from 1 subject. [From Eckberg (94).]
 CHAPTER 20: ARTERIAL BAROREFLEXES 761

age of 475 ms from the beginning of the pressure rise rate influence of the reflex can extend beyond the
(i.e., from the initial baroreceptor stimulation). Eck- stimulus.
berg (94) observed a shorter latency for this response. Clearly the relationship with the cardiac cycle and
In his study a suprathreshold stimulus to the carotid the fast adaptation rate phasically enhance the reflex
baroreceptors (neck suction) applied in the most sen- ability of controlling heart rate. The prolonged dura-
sitive portion of the cardiac cycle (see Fig. 2) initiated tion of the reflex effect, however, indicates that baro-
lengthening of the R-R interval after about 200 ms. receptor influence on heart rate can undergo temporal
Borst (43) disputed the results of Eckberg because his summation and therefore may provide more prolonged
neck suctions developed so quickly that the vagi might heart rate control. In this regard a single brief electri-
be mechanicallyactivated. Borst (43) published results cal shock to the carotid sinus produces R-R interval
from -1,OOO electrical stimulations of the carotid sinus effects that last long beyond the end of the stimulus
nerves on patients with angina pectoris suggesting [Fig. 4; (44)]. Thus the duration of reflex heart rate
that the latency between the electrical stimulus and effects after stimulation does not depend on persis-
the first R-R effect is at least 440-600 ms. Despite tence of excitation at the baroreceptor level but is
these differences all reports agree that in humans the determined at central and/or cardiac sites of the reflex
influence of arterial baroreceptor stimulation on heart arc.
rate can develop rapidly and provide the ability to
modulate the sinus node on a beat-to-beat basis. In- Relationship to Base-Line R-R Interval
terestingly studies on the interval between barorecep-
tor deactivation and the initial shortening of the R-R In their studies with phenylephrine-induced baro-
interval showed a slightly longer latency (4, 256). The receptor activation, Smyth et al. (307) observed that
longer latency does not reflect a different autonomic the sensitivity of the baroreceptor-heart rate reflex,
mediation because the response is also largely deter- calculated from the ratio between lengthening in R-R
mined, particularly in its earliest phase, by the vagus. interval and increase in systolic arterial pressure, was
As suggested by observations in animals, the latency directly related to the base-line R-R interval values.
may reflect an asymmetry of integrating processes of
the reflex at a central level (165).
The remaining properties that have mainly been
loo r
elucidated by the neck chamber technique (94,96) are
summarized as follows. 1 ) When a brief stimulus is
applied to the carotid sinuses, the lengthening in R-R
interval is maximal, considering the latency through
the reflex arc, with the arrival of the efferent reflex
effect 750 ms before the P wave. For arrival times
earlier than optimal, the effect decays linearly,
whereas for arrival times later than optimal, it decays
rapidly (Fig. 2). Thus the ability of the baroreflex to
affect heart rate largely depends on the timing of reflex
impact during the cardiac event, a finding well known
in animals (176, 195). 2) When a constant stimulus of
5 s is applied to the carotid sinuses, the reflex lengthen-
ing in R-R interval reaches a peak after 1.25 s but then
L
-20JlllL Time (s)
declines substantially through the duration of the ~~

stimulus (Fig. 3). Thus this reflex has a pronounced
adaptation rate. On the other hand, when a stimulus
is applied for a fraction of a second, its ability to
lengthen R-R interval, though declining after an initial
early peak, persists for several seconds. Thus the heart
0 1 2 3 4 5 6
FIG. 4. Prolongation of P-P interval evoked by electrical stimu-
lation of carotid sinus nerves for 300 ms. 0, Values during or after
stimulation; 0,control values in absence of stimulation. Stimulation
time indicated by vertical lines immediately below ordinate. Means
* SE from several observations. [From Borst and Karemaker (44).]

0.5 f A B J.F.
h -50 mmHg
y = 0.5%-1.1
FIG. 3. Effects of carotid baroreceptor stimuli for 5
r = -0.98 s on P-P interval. 0, Responses to single stimuli; A,
f' < O.Oo1 averages obtained at 0.5-s intervals. Baroreceptor
= 0.2 -
L . .. stimuii induced by neck suctions of 50 mmHg. Data
d from 1 subject. [From Eckberg (%).I
0.1 - .
'a
' 00.1
0 1 2 3 4 5 1 2 3 4 5
Stimulus to P wave interval (sec)
762 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111
Subjects with longer base-line R-R intervals had
higher baroreflex sensitivity and vice versa. This direct
relationship could also be seen in single subjects during
spontaneous or provoked alterations in base-line R-R
intervals. These observations were confirmed by sev-
eral others and are considered an established feature
of this reflex function (95, 345).
Selection of R-R intervals rather than heart rate to
express baroreflex sensitivity is partly responsible for
this direct relationship. Other factors are involved,
however. It is well known that sympathetic influences
may limit the cholinergic effects on the sinus node (99,
312). Thus, when long base-line R-R intervals reflect
less sympathetic influence, the lower sympathetic tone
probably makes the sinus node more responsive to
cholinergic baroreceptor modulation and vice versa.
Furthermore greater base-line R-R intervals may be
associated with a true increase in sensitivity of the
neural portion of the baroreflex arc. In neck chamber
studies on carotid baroreceptor stimulation, Eckberg
(95) showed that spontaneous increases in base-line
R-R intervals within a subject were associated with
striking increases in the baroreflex sensitivity, as cal-
culated from R-R interval responses. However, when
base-line R-R intervals were increased through exter-
nally applied continuous carotid baroreceptor stimu-
lation, the increase in baroreflex sensitivity with fur-
ther baroreceptor stimulation was much less evident.
This suggests that baroreflex sensitivity is the cause
and base-line R-R intervals are the effect within their
direct association, which implies that changes in ba-
roreflex sensitivity are the primary cause of sponta-
neous alterations in heart rate.
Relationship to Respiratory Cycle
Another feature of the arterial baroreceptor control
of heart rate is the dependence of its sensitivity on the
respiratory cycle, with a lesser value during inspiration
and a greater value during expiration. This phenome-
non is well known in animals (82, 149, 176), where it
has attracted interest as a mechanism for explaining
sinus arrhythmia. The first observation in humans was
made by Smyth et al. (307), who reported that the
linear relationship between the rise in systolic blood
pressure induced by vasopressor drug injections and
the reflex lengthening in R-R interval displayed a
greater slope if the values corresponding to the inspi-
ratory phase were not included.
More recently application of brief standardized
baroreceptor stimuli through neck suctions has added
considerable information. The ability of a barorecep-
tor stimulus to reflexly increase R-R interval was
greatly reduced during inspiration (44, 103, 104, 323).
However, this phenomenon did not take place as a
brisk shift but rather as a continuous oscillation
throughout the respiratory cycle (103).The sensitivity
was reduced most during early and midexpiration but
increased in late inspiration, reaching a maximum
level in the early expiratory period before declining
again. Thus, in addition to being continuous, the os-
cillations in baroreflex sensitivity were out of phase
with the inspiratory-expiratory periods (Fig. 5).
As to the mechanisms responsible for these oscilla-
tions, evidence was collected against interference on
baroreflex mechanisms by lung, thoracic, and cardiac
afferent fibers stimulated by changes in thoracic vol-
ume. A thoracic expansion obtained through assisted
ventilation did not depress the baroreflex sensitivity
(232). The inspiratory depression was not prevented
by eliminating thoracic expansion through a sudden
brief occlusion of the air tube connecting the mouth
to the spirometer (323).The depression still took place
and reproduced an approximate inspiratory rhythm
during voluntary apnea (323). The most likely hypoth-
esis is that central structures involved in breathing
rhythmicity interfere with the integrating mechanisms
of the baroreceptor-heart rate control. Recent data in
animals (227) and in humans (44, 104) suggest that
this interference is not exerted through a powerful
“gating” action that blocks the baroreceptor signal
centrally, as was previously supposed (200). Rather it
consists of an additive opposition between the central
and the reflex signals that may take place directly at
the level of the vagal cardioinhibitory neurons.
In discussing respiratory and baroreflex interac-
tions, the effects on the baroreflex of variations in
systemic Po2 and Pco2 should be considered. Reduc-
tion in systemic Po2 was not shown to consistently
alter the baroreflex sensitivity, although the increase
in base-line heart rate that resulted from the hypoxic
condition modified the set point of the reflex (51).
Although hypoxia is a complex stimulus, this finding
suggested that chemoreceptor stimulation did not pro-
duce major alterations in the extent of the carotid
baroreceptor influence on the sinus node. On the other
hand an increase in systemic P C Ocauses
~ a reduced
sensitivity of the baroreceptor-heart rate reflex, al-
though not consistently in all subjects, even when this
0’3 r Inspiration Expiration
I l l I I I
01 I I
0 1 2 3 4 5 6 7
Time (sec)
FIG. 5. Effects on P-P interval of carotid baroreceptor stimuli
applied at 6 different times during respiratory cycle. Baroreceptor
stimuli induced by neck suction of 30 mmHg for 0.6 s. Heart interval
responses calculated by subtracting maximal effects during stimu-
lation from base-line values in absence of stimulation. Data are
means f SE for 6 subjects. [From Eckberg et al. (103).]
 CHAPTER 20: ARTERIAL BAROREFLEXES 763

A 8

8.0
r

FIG. 6. A: marked depression of increase in heart (R-R) interval induced by carotid baroreceptor
stimulation during hypocapnic hyperventilation. B: lesser depression induced by hyperventilation
(Cod;
during isocapnia. From top: tidal volume (v); heart period (H.P.);endtidal 0 2 ; endtidal PCOZ
pressure within neck chamber (mmHg). Neck suction stimuli 1 and 4 applied before and after
hyperventilationduring resting breathing.Stimuli Band 3 applied during hypocapnic hyperventilation,
stimulus 5 during isocapnic hyperventilation with increased tidal volume, and stimulus 6 during
isocapnic hyperventilation with even more increased tidal volume. [From Tnebski et al. (3231.1

change was associated with hyperoxia to prevent ARTERIALBARORECEPTORCONTROLOF

chemoreceptor stimulation and when ventilation was
controlled (51, 52, 80). Interestingly a reduction in
sensitivity of the baroreceptor-heart rate reflex has
recently been reported in the opposite condition, i.e.,
during a reduction in systemic PCOZ[Fig. 6; (323)].
Lengthening in the R-R interval obtained through a
standardized carotid baroreceptor stimulus (neck suc-
tion) was drastically attenuated during hypocapnia
induced by hyperventilation. Hyperventilation per se
was not responsible for the attenuation, because when
PCOZ was kept constant the alteration in the baroreflex
response was much less evident. Thus either increases
or decreases in P C Omay
~ interfere with the barorecep-
tor-heart rate reflex. The site and the mechanisms of
this interference remain speculative. It is also uncer-
tain whether such interference involves only the car-
diac influence of the reflex or extends to its vasomotor
and blood pressure control. Data in animals, however,
indicate potentiation rather than depression of the
sympathetic vasomotor control exerted by
baroreceptors and cardiopulmonary receptors during
hypercapnia (119, 219, 249, 250).
ATRIOVENTRICULAR CONDUCTION
AND VENTRICLES
Arterial baroreceptors can exert a potent influence
on atrioventricular conduction, a feature vividly ex-
emplified by the atrioventricular blockade that is a
result of carotid sinus massage in some subjects (64,
130, 201, 357).
Only recently, however, the physiological control of
atrioventricular conduction exerted by the arterial
baroreceptors was demonstrated (207).In normal sub-
jects, His bundle potentials were recorded through
right cardiac chambers and atrioventricular conduc-
tion was evaluated in its two major components: I)
conduction through the atrioventricular node (A-H
interval, between atrial excitation and appearance of
His potential) and 2) conduction through the ventric-
ular portion of the atrioventricular conduction system
(H-V interval, between His potential and ventricular
excitation) [Figs. 7 and 8; (285)J Stimulation of arte-
rial baroreceptors by a 21-mmHg rise in mean arterial
pressure (phenylephrine injection), though causing a
764 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11

SINUS RHYTHM n = l l
R-R msec A-H m s e c H - V msec

11001 1001 801

I 1
60-

60 40
I 1 1 1 I l I I 1 I I 1
FIG. 7. Effects of phenylephrine-induced in-
creases in mean arterial pressure on R-R, A-H, and PACING n = l1
H-V intervals. Means & SE from 11 subjects stud-
ied for sinus rhythm and during atrial pacing. C, R - R msec A-H m s e c H-V m s e c
control values; PHE, values during plateau in- 1100
crease in mean arterial pressure induced by phen- 1401 T
ylephrine. [From Mancia et al. (207), by permission 1201
of the American Heart Association, Inc.]

gOOi 120-

100-
1
“1
500J
, ,
90
, ,
110
, I
130
I I

90
I I

110
I I

130
40 1- 90 110
I
130

MEAN ARTERIAL P R E S S U R E (mmHg)

700’
\ TNG
90;
601
I ent when the reflex alterations in R-R interval were
prevented by atrial pacing. A similar blood pressure
rise then caused a marked and sustained lengthening
in A-H interval, and a similar blood pressure fall

A - R msec A-H msec H - V msec

H-V interval. The reflex changes in A-H interval were
1 1 1
abolished by atropine.
These results show that arterial baroreceptors phys-
iologically exert a pronounced influence on atrioven-
tricular conduction and that this influence (like the
5OOJ
100 80 60
70J
100
111_1
80
1

60
40’
100
- 80
MEAN ARTERIAL PRESSURE ( m m H g )
FIG. 8. Effects of trinitroglycerin-induced reductions in mean
arterial pressure on R-R, A-H, and H-V intervals. Means & SE from
9 subjects studied for sinus rhythm (top) and during atrial pacing
(bottom). C, control values; TNG, values during plateau decrease in
mean arterial pressure induced by trinitroglycerin. [From Mancia
et al. (207), by permission of the American Heart Association, Inc.]
marked lengthening in R-R interval, did not induce a
lengthening in A-H and H-V intervals. Likewise deac-
tivation of the arterial baroreceptors by a 17-mmHg
reduction in mean arterial pressure (nitroglycerin in-
60
influence on sinus node function) is tonic and largely
mediated through vagal cholinergic mechanisms. In-
terestingly, although markedly modulating the atrio-
ventricular node, the baroreceptor influence does not
involve the ventricular portion of the atrioventricular
conducting system [results also reported in animals
(261)l. Furthermore the baroreceptor influence inter-
acts with the influence exerted on atrioventricular
conduction by the changes in cardiac cycle, the net
effect minimizing alterations in conduction time (24,
159,194,224). This suggests that arterial baroreceptor
modulation of the atrioventricular node is a homeo-
static mechanism that maintains a constant time re-
lationship between atrial and ventricular events during
reflex changes in heart rate.

Absence of baroreceptor control of the ventricular
portion of the atrioventricular conducting pathways
leads us to briefly discuss whether arterial barorecep-
tors have any effect on specialized ventricular con-
ducting tissue in humans. There are reports of various
arrhythmias following carotid sinus massage although
it is difficult to ascribe them to direct neural barore-
ceptor influences (68). Furthermore it has been re-
ported that ventricular tachycardias and ventricular
premature beats disappear during a pressure rise in-
duced by phenylephrine (347, 350). Although these
effects were ascribed to an increased vagal influence
on the ventricles brought about by baroreceptor stim-
ulation, other changes occurring with phenylephrine
injections might have been responsible. Indeed little
or no effect of phenylephrine injections was observed
on ventricular premature beats after preventing the
bradycardia induced by the injection with atrial pacing
(351). Furthermore no alterations in the rate of an
idioventricular pacemaker are known to follow baro-
receptor stimulation in subjects with a complete atrio-
ventricular block (201). Therefore available informa-
tion does not provide definite evidence for barorecep-
tor modulation of ventricular specialized fibers.
Direct effects of arterial baroreceptors on the ven-
tricles are possible because carotid sinus baroreceptor
stimulation exerts beneficial effects in patients with
angina pectoris (47, 107, 201). However, this benefit
may derive entirely from the reduction in cardiac work
and 0 2 consumption that accompanies the barorecep-
tor-induced hypotension and bradycardia. There is no
evidence of an arterial baroreceptor modulation of
ventricular contractility in humans, although the ef-
fect has been observed in anesthetized (145, 298) but
not in conscious animals (171, 334).
CAROTID BARORECEPTORCONTROL
OF BLOOD PRESSURE
Information on blood pressure control exerted by
the arterial baroreceptors is less extensive than that
on heart rate control, because invasive methods are
normally required to obtain proper estimation of reflex
blood pressure effects. Furthermore this information
is limited almost exclusively to the influence exerted
by the carotid baroreceptors, because there are no
techniques that allow blood pressure influences of all
arterial baroreceptors to be evaluated in humans. Nev-
ertheless a number of aspects of this control have been
investigated and clarified.
An important question is whether the carotid
baroreflex provides an effective blood pressure control
in response to physiological alterations in baroreceptor
stimuli. Studies performed several years ago showed
that ongoing activation of the carotid baroreceptors
exerted a clear-cut influence on blood pressure and, in
conscious normal subjects, abolition or drastic reduc-
tion of this activation by anesthesia of the carotid
CHAPTER 20: ARTERIAL BAROREFLEXES 765
sinus nerves or by occlusion of the common carotid
arteries was followed by a marked increase in pressure
(168, 273, 325). Other studies performed with neck
chambers on normal subjects confirmed and extended
these results. A reduction in carotid transmural pres-
sure of 15-20 mmHg induced a clear-cut increase in
blood pressure (214, 309, 321); conversely an increase
in carotid transmural pressure of 15-20 mmHg induced
a clear-cut fall in blood pressure (32, 109, 214, 309,
321). Physiological alterations in carotid baroreceptor
activity are therefore unquestionably capable of exert-
ing effective blood pressure control. In normal subjects
this control is tonic, which makes this reflex function
effective in response to both baroreceptor stimulation
and deactivation.
A second aspect is the latency and time course of
effective blood pressure control. In neck chamber stud-
ies, arterial pressure began to fall about 3 s after
baroreceptors were stimulated. If the stimulus was
kept constant, the fall in pressure reached a peak
within 10-20 s and then rose toward (but did not
reach) control values during the steady state (32, 43,
214). When carotid baroreceptors were deactivated,
the rise in pressure began after several seconds. If the
deactivation was kept constant, the pressure increased
slowly to a steady state in -20-30 s (214, 321). Thus
slowly developing effects, relatively long latencies, and
(in the case of baroreceptor deactivation) prominence
of the sustained over-the-peak responses were found
to characterize baroreceptor influences on blood pres-
sure. This contrasts with the baroreceptor influences
on heart rate. These features reflect the vascular sym-
pathetic mediation of the blood pressure effects of the
baroreceptors versus the vagal mediation of the heart
rate effects. They suggest that the baroreceptor-blood
pressure reflex has a considerable inertia; this may
prevent phasic alterations in baroreflex sensitivity
(e.g., during respiration) from being faithfully reflected
by alterations in blood pressure.
A third aspect is the quantitative control of blood
pressure provided by the carotid baroreceptors, which
could be estimated in a closed-loop condition by the
neck chamber technique (284), i.e., a condition in
which the reflex response reverberates on the recep-
tors and modifies the initial disturbance as normally
occurs. In normal subjects Mancia et al. (214) found
that the reflex pressor effect was in a linear relation-
ship with an increase in neck chamber pressure to +50
or +60 mmHg and that during the sustained phase of
the response the slope of the relationship, i.e., the
sensitivity or gain of the reflex function, indicated that
mean arterial pressure increased by an average of 0.68
mmHg/mmHg rise in tissue pressure outside the ca-
rotid sinuses. Application of correction factors for loss
of tissue-pressure transmission shows that in two pre-
vious studies average slopes of 0.68 and 0.72 were
obtained for the same response (309,321). These data
are strikingly similar to those of Mancia et al. (214).
They also found that reflex hypotension was linearly
766 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111
related to a reduction in neck chamber pressure to
-50 or -60 mmHg; the slope of the sustained response
indicated an average reduction in mean arterial pres-
sure of 0.44 mmHg/mmHg reduction in tissue pressure
outside the carotid sinuses. Application of correction
factors for loss of tissue-pressure transmission also
shows similarity to the average slopes obtained in
previous studies whose values ranged from a minimum
of -0.30 to a maximum of -0.50 for the same response
(32, 309, 321). Use of sinusoidal rather than steady
negative neck pressures provided a value of 0.40 (36).
Interestingly this slope was reported to be reduced
rather than increased by fitness in a comparison study
between trained and normal subjects (309).
In conclusion, the neck chamber studies, providing
closed-loop analysis of the carotid baroreflex, indicate
that the reflex can buffer about two-thirds and one-
half of the changes in arterial pressure that reduce or
increase, respectively, the baroreceptor activity. Aor-
tic baroreceptors may oppose the primary carotid
baroreceptor responses during prolonged interven-
tions with neck chambers, so these findings may un-
derestimate the carotid baroreflex control on arterial
pressure.
CAROTID BARORECEPTOR INFLUENCE ON
CARDIAC OUTPUT AND TOTAL
PERIPHERAL RESISTANCE
There is some controversy regarding the hemody-
namic changes responsible for the hypotension in-
duced by carotid baroreceptor stimulation, i.e.,
whether this effect is due to reduction in cardiac
output, total peripheral resistance, or both. During
electrical stimulation of the carotid sinus nerves,
Carlsten et al. (63) observed a reduction in pulse
pressure and argued that this implied a reduced car-
diac output. BevegHd and Shepherd (32) measured
cardiac output with a dye-dilution technique during
baroreceptor stimulation induced by neck suction in
normal subjects. Baroreceptor stimulation caused a
substantial reduction in mean arterial pressure, which
was accompanied by a fall in cardiac output (although
stroke volume did not change) with no significant
reduction in total peripheral resistance.
Although some reports (35) have been consistent
with those of BevegHrd and Shepherd (32), other stud-
ies have obtained somewhat different results. Epstein
et al. (107) observed that electrical stimulation of the
carotid sinus nerves in patients with angina pectoris
reduced cardiac output by 8%, but total peripheral
resistance was reduced by 14% and accounted for a
greater portion of the hypotensive effect of the stim-
ulus. Similar observations were made in anginal pa-
tients by Farrehi (114). Ernsting and Parry (109) and
Bjurstedt et al. (40) observed no change in cardiac
output during carotid baroreceptor stimulation in nor-
mal subjects and therefore ascribed the hypotensive
response entirely to a reduction in total peripheral
resistance.
No conclusion can be offered for these discrepancies.
A number of factors might influence the hemodynamic
pattern as well as the magnitude of the responses to
baroreceptor stimulation. The magnitude of the sys-
temic vasodilation induced by carotid baroreceptor
stimulation seems to differ as a function of age (198)
and possibly of central blood volume (35) and the time
course of the response. A decrease in cardiac output is
more likely to contribute to the early hypotensive
effect of baroreceptor stimulation (21, 43) but should
be less important in a later phase when the blood
pressure reduction seems independent of cardiac phe-
nomena.
The controversy regarding the hemodynamic pat-
tern of responses to baroreceptor stimulation does not
extend to the effects of carotid baroreceptor deacti-
vation, since in two studies on normal subjects a rise
in both cardiac output and peripheral resistance was
found to contribute to the pressor response (40, 325).
During a fall in blood pressure, an unchanged value
of peripheral resistance implies active withdrawal of
vasomotor tone (60). Therefore it can be concluded
that substantially all evidence indicates modulation of
resistance vessels by the carotid baroreflex and sug-
gests that in most subjects this is important in deter-
mining the size of the blood pressure response to either
baroreceptor stimulation or deactivation. Atropine
does not affect this response (43, log), which indicates
that cholinergic sympathetic fibers do not participate
in its production. Also plasma concentration of epi-
nephrine does not change, indicating that a humoral
adrenal factor is not involved (217). Modulation of
total peripheral resistance by the carotid barorecep-
tors therefore depends on alterations in sympathetic
vasoconstrictor tone.
ARTERIAL BARORECEPTOR CONTROL
OF REGIONAL CIRCULATIONS
Regional vascular control exerted by the arterial
baroreceptors has been mainly investigated in skeletal
muscle, the splanchnic area, and the skin.
Carlsten et al. (63) originally suggested the existence
of a pronounced baroreceptor influence over the vas-
cular bed of skeletal muscle. In anesthetized subjects
blood flow through the forearm (measured by a ple-
thysmograph) increased during hypotension induced
by electrical stimulation of the carotid sinus nerves,
indicating the occurrence of a marked vasodilation.
This suggestion has not been confirmed, however. In
studies on conscious normal subjects (32), during ca-
rotid baroreceptor stimulation by neck suction, a di-
lation of forearm blood vessels occurred only if marked
stimulation was applied. Even then the vasodilation
was less pronounced than that reported by Carlsten et
al. (63), and forearm blood flow did not increase during

the reduction in pressure. Other studies showed that
stimulation of the carotid baroreceptors by neck suc-
tion was also accompanied by little or no significant
reduction in forearm vascular resistance at a time
when other hemodynamic effects of the stimulation
were well evident (2, 5, 109). It must be emphasized
that these results could not be ascribed to the exist-
ence of a low sympathetic vasoconstrictor tone to the
forearm because little or no forearm vasodilation oc-
curred even when baroreceptor stimuli were applied
on a background of higher sympathetic vasoconstric-
tor tone (e.g., induced by exercise, lower-body suction)
(2, 25, 32, 35, 106). Furthermore forearm vasodilation
could be reflexly produced by raising the legs (5).Thus
it could be legitimately suggested that the results
reflected a truly limited ability of carotid barorecep-
tors to cause major sustained vasomotor effects in
skeletal muscle.
Studies supporting this suggestion have examined
the effects of carotid baroreceptor deactivation rather
than stimulation. In the 1950s (273) an important
study showed that during occlusion of the common
carotid arteries the rise in arterial blood pressure was
not accompanied by a rise in limb vascular resistance
(Fig. 9). Other investigators (160, 361) reported that
lower-body suction markedly increased forearm vas-
cular resistance and that only a minor further increase
could be seen when the suction became so pronounced
as to reduce arterial blood pressure. These observa-
tions suggest that cardiopulmonary baroreceptors
have a major influence and arterial baroreceptors a
minor influence on limb vascular resistance in humans.
0 1 rnin
FIG. 9. Effect of bilateral compression of common carotid artery.
Data from 1 subject. [From Roddie and Shepherd (273).]
CHAPTER 20: ARTERIAL BAROREFLEXES 767
A Forearm A Splanchnic
Vascular Resistance Vascular Resistonce
( % change) ( % change)
FIG. 10. Unloading of both cardiopulmonary and arterial baro-
receptors [lower-body negative pressure (LBNP) at -40 mmHg]
increased both forearm and splanchnic vascular resistances. Simul-
taneous application of neck suction (NS), performed to minimize
decrease in carotid transmural pressure and thus the contribution
of carotid baroreflex during LBNP, prevented most splanchnic
vasoconstriction but did not significantly attenuate forearm vaso-
constriction during LBNP. Results indicate that cardiopulmonary
receptors have major influence on forearm vessels, whereas carotid
baroreceptors have major influence on splanchnic vessels in hu-
mans. [Adapted from Abboud et al. (2).]
Different conclusions have been reached about the
baroreceptor control of splanchnic circulation. John-
son et al. (160) showed that lower-body suction that
did not reduce arterial blood pressure caused only a
moderate reduction in splanchnic blood flow [meas-
ured by hepatic clearance of indocyanine green (46,
277)]. On the other hand a marked reduction in this
flow, and thus a marked increase in splanchnic vas-
cular resistance, was observed when the suction was
augmented to a degree that reduced pulse pressure
and mean arterial pressure. Also simultaneous stimu-
lation of the carotid baroreceptors during lower-body
suction had different effects on the skeletal muscle
and splanchnic circulations (2). The marked skeletal
muscle vasoconstriction induced by lower-body suc-
tion was little affected by the carotid baroreceptor
stimulus, whereas the splanchnic vasoconstriction was
almost completely abolished (Fig. 10). Thus, although
little involved in the control of muscle resistance ves-
sels, arterial baroreceptors exert a clear-cut control
over resistance vessels in the splanchnic area. This
means that the vasomotor control of these receptors
is quantitatively nonuniform, which is opposite to the
nonuniformity displayed by the vasomotor control
exerted by the cardiopulmonary receptors.
The limited baroreceptor influence on muscle cir-
culation that appears to exist in human beings makes
us strikingly different from several other animal spe-
cies in which this circulation represents a major target
organ for the baroreflexes (166,219,247,248,270,333).
Recent findings suggest, however, that this difference
may be viewed from a different perspective. Tyden et
al. (328) observed in anesthetized subjects that a mas-
sive baroreceptor stimulus (carotid sinus massage),
though causing very little vasomotor change in various
intestinal areas, increased blood flow (electromagnetic
flow probe measurement) to the external iliac artery
and decreased the resistance in this vascular area by
768 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11
29%. This suggests that baroreceptors do not lack the
potential for exerting pronounced effects on skeletal
muscle circulation in humans.
Skeletal muscle circulation may also be under phys-
iological baroreceptor control according to data on
sympathetic nerve traffic to skeletal muscle vessels.
Wallin and co-workers (83, 310, 340) observed in con-
scious subjects that this traffic definitely decreased
with a latency of -1 s on the ascending phase of each
pulse-pressure wave and increased to an even greater
extent during the descending phase (Fig. 11). Further-
more application of neck suction or electrical sinus
nerve stimulation induced a clear-cut reduction in
muscle sympathetic nerve traffic (22,341). If the stim-
ulus was steady, the reduction was only transient and
the traffic rapidly regained the control value even
though the hypotensive response was preserved. On
the other hand, if the stimulus was applied in a con-
tinuously changing fashion (sinusoidal neck suction
for 7.5 s), a steady reduction in muscle sympathetic
traffic was also observed (22). Thus the possibility
must be considered that arterial baroreceptors nor-
mally control skeletal muscle circulation, but this con-
trol exclusively has a highly dynamic feature with
little possibility of being used to induce more pro-
longed circulatory effects. Therefore it may be specu-
lated that baroreceptor control of muscle areas may
be suited to and attend predominantly to rapid and
short-lasting adjustments in blood pressure, leaving
the steadier adjustments to baroreceptor influences on
splanchnic and other vascular areas.
In their investigation of the effects of common ca-
rotid occlusion, Roddie and Shepherd (273) also stud-
ied the cutaneous circulation by measuring skin blood
flow from 0 2 saturation in veins draining from super-
ficial hand tissues (274). They observed no alterations
in skin vascular resistance during baroreceptor deac-
tivation induced by carotid occlusion and suggested a
FIG. 11. Bursts of muscle sympathetic efferent traffic (upper trace) during oscillations in arterial
blood pressure (lower trace). More bursts occurred during decreasing than during increasing blood
pressure values when latency for reflex sympathetic modulation (1.3 s) was taken into account. [From
Sundlof and Wallin (310).]
lack of baroreceptor modulation of cutaneous vascular
districts (see Fig. 9). In a subsequent study, however,
evidence for some baroreceptor modulation of cuta-
neous circulation was obtained (25). Forearm skin
blood flow was measured by the difference in flow
between an intact forearm and a forearm in which
cutaneous circulation had been eliminated by epineph-
rine iontophoresis (71). During lower-body suction the
reduction in arterial blood pressure was accompanied
by a reduction in skin blood flow and an increase in
skin vascular resistance. Conversely during barorecep-
tor stimulation produced by neck suction the hypoten-
sive response was accompanied by no change in skin
blood flow and a decrease in skin vascular resistance.
The cutaneous vascular response to performance of
lower-body suction could not be safely ascribed to
arterial baroreceptor deactivation because of concom-
itant deactivation of the cardiopulmonary receptors
(230, 278). However, the skin vascular response to
neck suction was probably the result of baroreceptor
stimulation although the participation of autoregula-
tory phenomenon [even though poorly developed in
the skin (135)l and emotional stimuli could not be
excluded.
Studies of baroreceptor influence on sympathetic
nerve traffic to skin tissues have shown that this traffic
was not consistently altered during the pulse-pressure
waves (at variance with the muscle nerve traffic) and
that its random and irregular firing rate was not re-
duced even during the massive baroreceptor activation
provided by electrical carotid sinus nerve stimuli (83,
339, 341). Obviously this supports the suggestion that
arterial baroreceptors do not have major effects on
the cutaneous circulation, although it does not prove
this point conclusively. As discussed by Wallin et al.
(341), the cutaneous fibers engaged in reflex vascular
control may be a minority among tonically active
fibers engaged in vascular thermoregulation or sudo-
- 5 sec

motor influences, which may make it difficult to detect
changes in sympathetic traffic induced by barore-
flexes.
Clarifying baroreflex influences on skin blood ves-
sels may be difficult because of the complexity of the
neural regulation of the cutaneous circulation. Acral
and nonacral regions may be differently engaged by
neural impulses, and different reactions may be seen
at different levels of thermoregulatory-induced vaso-
constrictor tone (296). Thus further studies under
controlled conditions in various regions of skin may be
needed to decide whether and to what extent skin
resistance vessels participate in arterial baroreflexes.
ARTERIAL BARORECEPTOR
CONTROL OF VEINS
In animals, arterial baroreflexes do not exert a ma-
jor control of cutaneous veins (49, 58, 146, 208). De-
spite earlier reports (128,251,292) this also appears to
be true in humans. Beveghd and Shepherd (32) stud-
ied responses of a hand vein to neck suction. Veno-
motor changes were evaluated by using the occlusion
technique, which allows pressure within a vein to be
measured under conditions in which venous volume is
constant (280). Baroreceptor stimuli even of a large
degree (neck suction of -60 mmHg) did not reduce
venous pressure. This did not depend on lack of reac-
tivity of the veins to neural stimuli, because a marked
increase in venous pressure was observed during a
deep breath, i.e., a stimulus known to reflexly affect
venous tone (42). It did not depend on absence of
base-line venoconstrictor tone, because reflex venodi-
lation was not observed even when base-line venocon-
striction was induced by exercise (33). Therefore the
results truly reflected absence of reflex venodilation
during stimulation by carotid baroreceptors.
Epstein et al. (108) extensively examined the arterial
baroreceptor influences on cutaneous veins. By ex-
amining venomotor tone with various techniques these
investigators found that I ) stimulation of carotid
baroreceptors by neck suction did not cause venodi-
lation, 2) stimulation of all arterial baroreceptors by a
phenylephrine-induced rise in arterial pressure also
did not cause venodilation, and 3) arterial barorecep-
tor deactivation by bradykinin or nitroglycerin some-
times caused an initial brief venoconstriction. This
transient venoconstrictor response was not seen in
anesthetized subjects, however, and it appeared to be
related to emotional stimuli involved in the experi-
mental maneuver. Also in this study the reactivity of
the vein was demonstrated by the response to a deep
breath (Fig. 12).Thus it may be concluded that arterial
baroreceptors do not exert a modulation of the cuta-
neous veins within their physiologicalrange of activity.
The same conclusion has been reached in several other
studies that have shown absence of venomotor
changes in both forearm and calf during simultaneous
CHAPTER 20: ARTERIAL BAROREFLEXES 769
engagement of arterial and cardiopulmonary reflexes
(3, 124,260, 281). In contrast to observations on cuta-
neous veins, splanchnic capacitance vessels in animals
participate in the cardiovascular regulation exerted by
the arterial baroreceptors (49, 57, 143, 297, 299, 300).
Lack of suitable techniques has so far prevented defin-
itive information on this topic in humans. However,
stimulation and deactivation of the carotid barorecep-
tors have produced no change in central venous pres-
sure (106,109,273). Thus there is presently no definite
evidence for baroreceptor influences on the veins in
humans.
SET POINT OF CAROTID BAROREFLEX
Several studies have reported that when carotid
baroreceptor control of blood pressure is examined by
applications of positive and negative neck pressure,
the sustained blood pressure responses to baroreceptor
deactivation are greater than the responses to baro-
receptor stimulation (214, 309, 321). If the barorecep-
tor stimuli are corrected for loss of tissue-pressure
transmission (204),the sensitivity of the baroreceptor-
blood pressure function appears to be -48% greater
during baroreceptor deactivation than during barore-
ceptor activation [Fig. 13; (214)]. A number of hy-
potheses have been proposed to explain this finding.
1. Arterial baroreceptor modulation of muscle sym-
pathetic traffic is greater during each pulse-pressure
wave when blood pressure falls than when it rises (310,
340); i.e., this modulation has a hysteresis that appears
to favor the reflex responses to baroreceptor deacti-
vation rather than stimulation. Hysteresis is typically
a transient phenomenon, however, which cannot ac-
count for sustained hemodynamic differences. Fur-
thermore the sustained blood pressure influences of
the baroreceptors are largely independent of changes
in muscle circulation (2,5). Therefore this hypothesis
probably cannot explain the asymmetry of the carotid
baroreceptor effects on blood pressure.
2. In normotensive subjects, aortic baroreceptors
may discharge basally near their maximal level, thus
more effectively buffering the depressor responses ob-
tained by carotid baroreceptor stimulation than the
pressor responses obtained by carotid baroreceptor
deactivation. Studies in animals, however, have never
shown the aortic baroreceptors to be nearly maximally
stimulated at normal blood pressure levels. On the
contrary, they have shown these receptors to be barely
at threshold at normal blood pressures (252, 319, 320)
and to provide greater buffering effects against blood
pressure rises than falls (85,105,147).Furthermore no
hint of a high tonic level of aortic baroreceptor activity
has been derived from studies in humans (141). This
hypothesis also cannot explain the carotid baroreflex
asymmetry.
3. The most likely hypothesis is therefore that the
asymmetry is inherent to the carotid baroreflex. In
770 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111

HEART RATE VENOUS PRESSURE, occluded limb

beats / min m m Hg

I
I00

80 -8 30 -

60 - 20 -

FIG. 12. Increase in pressure induced 40 - IO-

by phenylephrine (upper traces) and re-
duction in pressure induced by bradyki-
nin (lower traces) accompanied by
' A , 0 - 0

120
bradycardia and tachycardia, respec-
tively, but by no change in tone of cuta- Control Phenylephrine Control Phenylephrine Control k P
neous veins. Right panel shows reactiv- Insp i r a t ion
ity of veins by constriction after deep
inspiration. Each line, 1normal subject. beots / min mrn Hg
m m Hg

i
[From Epstein et al. (108),by copyright I

I
permission of The American Society for
Clinical Investigation.]

100-
40

30-
401
30 -

20 -
80 -

701 Y
*\*
-
e
0
60. 10-

lo :

Control Bradykinin Control Br o dy k I n'in Cont ro I Inspiration

NORMOTENSIVES ( n = 11) other words, in normal subjects the set point of this
reflex is eccentrically located toward the saturation
+ "1 1
limit of the curve relating the carotid baroreceptor
stimulus to the blood pressure effect. This should
make the baroreflex system more effective for buffer-
ing a reduction rather than an increase in blood pres-
sure. It can be speculated that this location of the set
point depends on a high basal activity of the carotid
sinus baroreceptors because of their sensitivity to pul-
satile stimuli at normal blood pressures (7, 10, 77, 92,

1 :Steady-State
Transient
185) and because of their location in a vascular wall
with reduced thickness, greater elasticity, and presum-
ably large distensibility (170, 237, 267, 268).
-60 A discussion of the normal set point of the arterial
Change in NTP (mmtig) baroreflex in humans must include a recent study by
Eckberg (98) in which negative and positive neck
FIG. 13. Changes in mean arterial pressure (MAP) induced by pressures were applied to normal subjects and the
changes in neck tissue pressure (NTP) outside carotid sinuses. Data reflex changes in R-R interval were evaluated within
are means f SE of individual regression coefficients in 11 normal
subjects for sustained responses to steady neck chamber pressure 1-2 s, i.e., before any alteration in arterial blood pres-
or suction applications. [From Mancia et al. (214), by permission of sure could engage the aortic baroreceptors. The heart
the American Heart Association, Inc.] rate responses were marked with negative pressure

but slight or absent with positive pressure. Based on
these results Eckberg (98) argued that the normal set
point of the carotid baroreceptor-heart rate reflex is
located near the reflex threshold, i.e., in a position
opposite to that suggested for the carotid barorecep-
tor-blood pressure reflex. Note that in conscious ani-
mals carotid baroreceptor deactivation by common
carotid occlusion or other methods invariably induces
a marked rise in blood pressure and heart rate (16,73,
113, 171). Carotid baroreceptor deactivation by com-
mon carotid occlusion or anesthesia of the carotid
sinus nerves is associated with a marked rise in blood
pressure and heart rate in anesthetized and conscious
normal humans (59, 155, 168, 266, 273). Baroreceptor
deactivation by a drug-induced fall in blood pressure
causes a clear-cut tachycardia in conscious normal
humans (184, 193, 214, 256, 272). These findings can
hardly be reconciled with those of Eckberg, because
they suggest that arterial and, more specifically, ca-
rotid baroreceptors are normally well above threshold
and accordingly have a marked tonic influence on both
blood pressure and heart rate.
AORTIC BAROREFLEXES
There is no f m experimental evidence in this re-
view concerning the selective influence of aortic
baroreceptors in the human cardiovascular system,
because there are no techniques with which to study
them. It may be useful, however, to discuss some of
the studies that have reached inferred conclusions on
this control and to compare them with conclusions
provided by the more easily controlled studies done
with experimental animals.
Mancia et al. (211,214) examined in normal subjects
the reflex heart rate responses induced by stimulation
and deactivation of the arterial baroreceptors by phen-
ylephrine and nitroglycerin, respectively. The results
were compared with those obtained in the same sub-
jects by stimulating and deactivating the carotid ba-
roreceptors with negative and positive neck pressure.
With phenylephrine the baroreceptor control of heart
rate induced a steady lengthening in R-R interval
averaging 14.4 ms/mmHg increase in mean arterial
pressure (Fig. 14). On the other hand, with negative
neck pressure the sensitivity was much less, i.e., a
lengthening in R-R interval of 4.5 ms/mmHg increase
in carotid transmural pressure. With nitroglycerin the
baroreceptor control of heart rate induced a steady
shortening in R-R interval of 9.5 ms/mmHg reduction
in mean arterial pressure, whereas with positive neck
pressure the shortening was only 3.6 ms/mmHg re-
duction in carotid transmural pressure. Among the
several factors that might be responsible for the
greater heart rate responses to the drug injection than
to the neck chamber application, the following were
excluded: I ) pulse pressure did not show change with
either technique; 2) the doses of phenylephrine nor-
mally used did not approach those considered to stim-
CHAPTER 20: ARTERIAL BAROREFLEXES 771
n
0
Q
-5001
v)
E
z-
- d
a
w>
U a
+
z w
a+
IZ
0- t
+
a
a
W
I
L+ 500
CHANGE IN MAP CHANGE IN C T P
(mmHg) (mmHg)
FIG. 14. Changes in heart interval (R-R interval) with drug-
induced alterations in mean arterial pressure (MAP) and with neck
chamber-induced alterations in carotid transmural pressure (CTP).
*
Means (solid lines) SE (dashed lines) of individual regression
coefficients taken from 8 normal subjects in whom both techniques
were used. Maximal heart interval responses were considered for
neck chamber, with changes in CTP calculated by subtracting
changes in MAP from changes in tissue pressure outside carotid
sinuses. Method described by Korner et al. (184) was used for drug
technique. Control MAP and heart interval were 101 f 5 mmHg
and 864 -+ 61 ms, respectively, for drug studies and 105 f 5 mmHg
and 791 f 59 ms for neck chamber studies. [From Mancia et al.
(214), by permission of the American Heart Association, Inc.]
d a t e baroreceptors by direct contraction of vascular
smooth muscle (31), and the heart rate responses were
also greater with nitroglycerin than with neck pres-
sure; 3) the time for the pressor and depressor drug
stimuli to reach steady heart rate responses was less,
rather than more, than the corresponding time for the
increases and decreases in carotid transmural pressure
by the neck chamber; and 4 ) equal changes in arterial
transmural pressure are known to affect arterial
baroreceptors similarly when produced from inside
(drugs) or from outside (neck chamber) the vessels
(8).
The most likely explanation is that heart rate re-
sponses with the drug technique were greater than
responses with the neck chamber because the stimulus
to all arterial baroreceptors is similar with the drug
technique, whereas changes in neck pressure can pro-
duce opposing effects on carotid and aortic barorecep-
tors. The difference observed could thus suggest the
existence of an aortic baroreceptor control of heart
rate. Furthermore the magnitude of the difference
could imply a qualitatively important control, and its
existence during both baroreceptor stimulation and
deactivation could imply a tonic nature. Interestingly
several studies in animals have indicated that aortic
baroreceptors exert a large reflex influence on heart
rate (81, 132), and some have suggested that this
control may be greater than that exerted by the carotid
baroreceptors (151, 288, 356). Because in animals the
heart rate responses to carotid sinus stimulation are
smaller and are not sustained (32,43,109,214),Mancia
772 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11

et al. (214) have suggested that this baroreceptor area if the carotid sinus influence is not reduced or removed
normally exerts only a modest heart rate control in (105, 139, 208, 247). The role of aortic baroreceptor
humans. However, these features may be explained by control of blood pressure in humans therefore remains
the adaptation rate of the heart rate responses (96), to be elucidated.
and several recent findings do show the ability of the
carotid baroreceptors to produce heart rate alterations
(2, 22). Therefore reflex control of this variable prob- FACTORS THAT MODIFY ARTERIAL
BARORECEPTORCONTROLOFCIRCULATION
ably stems from both baroreceptor areas.
The only studies that can be mentioned in relation
to blood pressure control exerted by the aortic baro- Age
receptors are those of Guz et al. (141, 142). In a small Gribbin et al. [Fig. 15; (138)l obtained the first
number of anesthetized and conscious normal sub- evidence of an effect of age on the arterial baroreceptor
jects, these investigators applied electrical stimuli to control of heart rate. In this study the ramp method
the cervical vagal trunks after blocking their efferent was used to evaluate baroreceptor-heart rate sensitiv-
influence by atropine. The stimulation had clear-cut ity in response to baroreceptor stimulation by vaso-
respiratory effects but did not cause any fall in blood active drugs. Among the normal subjects baroreflex
pressure. In the same subjects the vagi were infiltrated sensitivity varied, but within the wide age range of the
with an anesthetic agent. Several observations (in- sample (19-66 yr) the sensitivity was inversely related
ability to phonate or swallow, disappearance of the to age. There was no trend in these subjects toward
cough in response to reflex ammonium inhalation, an increased base-line blood pressure with age. The
appearance of a Horner syndrome) indicated effective same inverse relationship between reflex sensitivity
blockade of vagal fibers, but there was no increase in and age occurred in a separate population of hyperten-
blood pressure. Based on these findings, Guz et al. sive subjects. Thus it may be concluded that age
suggested that aortic baroreceptors do not exert a impaired the heart rate effect of baroreceptor stimu-
tonic blood pressure control and that even their acti- lation and that this was independent of the well-known
vation may have minimal blood pressure effects. Min- influence of hypertension (55, 138).
imal cardiovascular control from reflexogenic areas This conclusion has been confirmed in studies with
with vagal afferents has also been suggested in sub- vasoactive drugs (184, 265, 302, 345), the Valsalva
human primates (129). However, the negative findings maneuver (90),tilting (245, 353), and neck chamber
of Guz et al. (141,142) cannot be easily reconciled with (198). Interestingly Korner et al. (184) used vasoactive
the evidence in humans that cardiopulmonary recep- drugs and measured baroreflex sensitivity from the
tors participate importantly in cardiovascular control. steady-state heart rate responses. During both baro-
Perhaps no responses to vagal blockade were found receptor stimulation and deactivation, baroreflex sen-
because afferent vagal fibers with pressor and depres- sitivity was less in older subjects. This reduction was
sor influences were stimulated simultaneously or be- much more marked than that reported by Gribbin et
cause the blood pressure effects of the vagal blockade al. (138). In subjects with a mean age of 43.9 yr the
were buffered by the carotid sinus baroreceptors. In sensitivity (cumulatively calculated for baroreceptor
animals in which aortic and cardiopulmonary reflex stimulation and deactivation) allowed the R-R inter-
control of circulation exists, vagal or aortic nerve val to change 21 ms/mmHg variation in mean arterial
blockade does not cause major hemodynamic effects pressure. This value was only 51% of the value ob-

- r 2.0 NORMOTENSIVE r - 0.739 p<O.OOl

Y o HYPERTENSIVE r * 0.621 p<O.OOl
-n
0
H
* *
-:e - 8
->.1.5
-I
*\-
I-

FIG. 15. Effect of age on baroreflex sensitivity in

normotensive and hypertensive subjects. Baroreflex =~57,
sensitivity expressed (uertical line) as logarithm of
slope relating increase in R-R interval and rise in
systolic blood pressure induced by phenylephrine.
$
[From Gribbin et al. (138), by permission of the Amer- -
y
;can Heart Association, Inc.] . LL

0"
0
0.5
0
e l 0
0

m I
L I I 1 1 1 1
10 20 30 40 50 60 70
ACE ( y e a r s )

served in subjects with a mean age of 23.5 yr. Similar
profound effects of age on baroreflex sensitivity were
found in subjects with moderate hypertension,
whereas age did not reduce the baroreflex sensitivity
in subjects with severe hypertension much below the
low value already induced by the hypertension itself.
In the latter group, however, aging was associated with
a marked reduction in the difference between the
maximal bradycardia and tachycardia achieved with
baroreceptor stimulation and deactivation, respec-
tively (Fig. 16). These findings indicate that age is a
primary factor in determining the effectiveness of
baroreceptor control of heart rate.
Effects of age on baroreceptor control of peripheral
= 1200-
I (large black circle) and by calcu-
Age range 32-57years
- lating heart interval during
IOOO-
-
800-
Group1 f
Group 2
600-
-
tA'
CHAPTER 20: ARTERIAL BAROREFLEXES 773
circulation have been studied recently in 15 normal
subjects younger than 30 yr and in 15 normal subjects
older than 30 yr (198). Base-line blood pressure, car-
diac index, total peripheral resistance, body weight,
and other factors were matched between the two
groups. In the younger group neck suction induced an
average reduction in mean arterial pressure of 11.5
mmHg, a decrease in cardiac index, and an average
reduction in total peripheral-resistance index of 0.4
units. In the older group the reduction in cardiac index
produced by neck suction was not significantly differ-
ent from that of the younger group, but decreases in
mean arterial pressure and peripheral resistance were
significantly less.
cerin injection) mean arterial
pressure from base-line value
steady-state phase of response.
Data are means f SE for several
subjects [From Korner et al.
(1W.I
774 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11

Thus the whole cardiovascular regulation exerted
by the arterial baroreceptors apparently is progres-
sively impaired with aging, which might at least partly
explain why blood pressure varies more in older sub-
jects than in younger ones (212).
The age-dependent reduction in baroreceptor-car-
diovascular control conceivably might be caused by
stiffening of the arterial walls where the receptors are
located (17, 134, 191). Indeed an inverse relationship
between baroreflex sensitivity and age and arterial
compliance has been shown (264). However, heart rate
responses to a variety of interventions are reduced at
older ages possibly because of reduced cardiac respon-
siveness (187). Thus nonspecific alterations in the
neuroeffectors may be at least partly responsible for
the reduction of baroreceptor sensitivity.
Exercise
There are three consistent reports on the effects of
exercise on blood pressure control exerted by the
arterial baroreceptors. In subjects with angina pectoris
Epstein et al. (107) electrically stimulated the carotid
sinus nerves at rest and during mild exercise and
observed that the absolute decreases in mean arterial
pressure and total peripheral resistance that followed
the stimulus were slightly reduced or unchanged dur-
ing the mild exercise. In normal subjects Bevegdrd
and Shepherd (32) stimulated the carotid barorecep-
tors by neck suction. The stimuli were applied during
three dynamic exercises that increased from mild to
moderate intensity. The decrease in arterial pressure
and vascular resistance during baroreceptor stimula-
tion was similar in the three conditions (Fig. 17).
Ludbrook et al. (203) stimulated and deactivated the
carotid baroreceptors (using neck chambers) during
three levels of isometric exercise. The responses to
baroreceptor stimulation and deactivation were not
altered by exercise. It can therefore be suggested that
in humans carotid baroreceptor control of blood pres-
sure is substantially preserved during exercise of either
a dynamic or static type. Moreover, particularly as
suggested by the observations of Ludbrook et al. (203),
this control may be reset at the higher pressure levels

NECK SUCTION NECK S U C T I O N

+. *'
- 5 0 m m Hg

HEART RATE
(kotr/mlnutr 1
100

80

MEAN RADIAL ARTERY loo

PRESSURE I m m . n g l
80

6
FOREARM BLOOD FLOW
(mi. / I 0 0 ml. / m I n . )

40
FOREARM VASCULAR Jo
RESISTANCE (Units)
20

.-
I0
LEG E X E R C I S E : 2 7 0 kg.-m./mln. 5 4 0 hg.-m./mfn. 810 kq-m./min.
0 1 2 3 4 5 0 1 2 3 4 5 0 1 1 3 4 5
minutes
FIG. 17. Effects of carotid baroreceptor stimulation by neck suction on hemodynamic variables at
different levels of dynamic leg exercise in supine position. Data are means for 6 normal subjects. Note
well-preserved blood pressure reductions during baroreceptor stimulation. Heart rate reductions also
evident but with some attenuation at greatest exercise level. [From Beveglrd and Shepherd (32), by
copyright permission of The American Society for Clinical Investigation.]
 CHAPTER 20: ARTERIAL BAROREFLEXES 775

that accompany exercise. The resetting and the un-
changed sensitivity of this baroreflex function might
contribute to the stabilization of the elevated blood
pressure values that occur during exercise.
The results of studies on baroreceptor control of
heart rate during exercise are less consistent. Bevegird
and Shepherd (32) observed that the bradycardia pro-
duced by carotid baroreceptor stimulation was unal-
tered or only moderately reduced during mild or mod-
erate dynamic exercises (Fig. 17). Robinson et al. (272)
made similar observations in studies of the brady-
cardic effect of arterial baroreceptor stimulation by
phenylephrine and the tachycardic effect of arterial
baroreceptor deactivation by amyl nitrate. These find-
ings suggested that baroreceptor control of heart rate
is also largely preserved during exercise. This concept
has been challenged in a series of studies performed
by investigators in Oxford (53, 79,257, 258). Using the
ramp method for calculating baroreflex sensitivity,
they found that the slope of the relationship between
the lengthening in R-R interval and the rise in systolic
or mean arterial pressure (phenylephrine injection)
was reduced during dynamic exercise and particularly
during isometric exercise. The reduction was directly
related to the severity of exercise (Fig. 18). In a few
subjects the slope relating shortening in R-R interval
to a decrease in blood pressure (amyl nitrate inhala-
tion) was also reduced during exercise.
The Oxford group used R-R interval rather than
-I I I 1 I I
heart rate to express the baroreflex response (53).
During exercise there is a progressive increase in base-
line heart rate, so that progressively smaller increases
in R-R interval are required to obtain a given heart
rate response. If expressed as R-R interval the re-
sponses obtained by Bevegird and Shepherd (32) and
by Robinson et al. (272) were markedly reduced during
exercise. Thus one difference in these studies relates
to the method of calculating the baroreflex responses.
This is not the only explanation, however. Tachycar-
dias produced by infusion of isoproterenol, though
reducing the slope of the responses, did not have an
effect as profound as that observed for corresponding
tachycardias during exercise. No matter how the re-
sponses were expressed, a reduction was observed at
the more severe degrees of exercise, and R-R interval
or heart rate changes were almost abolished when
exercise reached a level corresponding to a base-line
tachycardia of -150 beats/min. Moreover responses
were also reduced a few seconds after the beginning of
exercise, before clear-cut changes in base-line heart
rate had occurred (53). Thus there appears to be an
impairment of arterial baroreceptor control of heart
rate, particularly with severe degrees of exercise. This
conclusion has recently been supported by Mancia et
al. (216) and by Ludbrook et al. (203), who found this
control (measured by heart rate changes) to be im-
paired at the beginning of isometric exercise. This
impairment may favor achievement of high heart rates
during exercise.
By what mechanisms can exercise reset the arterial
baroreflex and impair its heart rate influence while
leaving its blood pressure control relatively unaf-
fected? There is little doubt that the reduction in
sensitivity of the baroreceptor-heart rate reflex during
exercise may partly reflect interaction between vagal
and sympathetic influences at the sinus node (126,
127, 275). It is conceivable, however, that the modu-
lation of the baroreflex during exercise is also elicited
through descending hypothalamic influences. In ani-
mals hypothalamic influences may modulate barore-
flex control of heart rate without exerting much effect
on baroreflex control of blood pressure (222).

Mental Stress
, Sleight et al. (305) examined the bradycardic effect
-
A -
of arterial baroreceptor stimulation by phenylephrine
in three normotensive and four hypertensive subjects
L I I 1 I I
before and during stressful mental arithmetic. Baro-
so 100 150 reflex sensitivity was invariably reduced during the
test, the average value being about 55% of the sensi-
Systotic pressure, mm Hg tivity obtained during control conditions. Blood pres-
FIG. 18. Slope of linear regression (lines) between increases in sure increased slightly and heart rate increased mark-
systolic blood pressure induced by phenylephrine and resulting edly during the test. The increase in heart rate may
lengthening in pulse interval (R-R) interval. Data from several have contributed to the reduction in the reflex re-
subjects studied at rest and at progressively increasing work loads sponse, but the profound reduction suggested that
(dynamic exercise). Slopes of baroreflex control of heart interval
progressively diminish and flatten at greatest exercise levels. [From mental stress had an independent depressant effect.
Bristow et al. (53),by permission of the American Heart Association, The effects of mental stress on the baroreflex have
Inc.] recently been studied in 12 normal subjects by Lind-
776 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111

blad (199). Steady neck suction of -40 mmHg was ceptor-heart rate reflex turned out not to be a gener-
applied before and during a “color-word conflict’’ that alized phenomenon: among 15 subjects an increase in
consisted of asking the subjects to rapidly single out the baroreflex sensitivity during slow-wave sleep was
relevant information from contrasting audiovisual re- found in only 4 subjects, in 6 others the sensitivity was
ports. During control, neck suction decreased blood not significantly altered during sleep, and in 5 it was
pressure and heart rate. During the test, base-line decreased. In almost all subjects, however, the asso-
blood pressure and heart rate increased as a result of ciation between base-line bradycardia and hypoten-
the stress. However, the heart rate and blood pressure sion and persistence of heart rate responses to baro-
responses to baroreceptor stimulation were similar to receptor stimulation suggested that the stimulus-re-
those obtained in the control condition. sponse curve of the reflex had been displaced during
There is much to be learned about the relationship sleep toward a lower blood pressure range, i.e., it had
between mental stresses and arterial baroreflexes. Dif- been reset in a direction opposite to the resetting that
ferences in this relationship may exist according to the occurs in hypertension (358).Baroreflexes can be reset
nature of the emotional stimulus and the particular by reductions (as well as by increases) in arterial blood
cardiovascular response. Note that in animals the pressure in animals also (279).
hypothalamic descending influences involved in regu- Smyth et al. (307) and Bristow et al. (54) have
lation of emotional cardiovascular responses impair discussed the implications of these findings. Because
arterial baroreflex control of heart rate more than they of resetting and in some subjects an increased sensi-
modulate baroreceptor control of vascular resistance tivity, the arterial baroreflexes may actively and effec-
and blood pressure (222). tively defend rather than buffer the lower heart rate
and blood pressure values induced by the neural de-
Sleep pressor influences of sleep (221). Two studies are nec-
essary to test this hypothesis. 1 ) Observations are
In the original study describing the ramp method needed on the sensitivity of the arterial baroreflex
for evaluating heart rate responses to arterial barore- during baroreceptor deactivation rather than stimu-
ceptor stimulation, Smyth et al. (307) investigated lation, because this is the baroreceptor function spe-
alterations in sensitivity of this baroreflex function cifically engaged during the fall in blood pressure
during sleep. In normotensive and hypertensive during sleep. 2) The effects of sleep on baroreflex
subjects blood pressure was measured intraarterially control of the blood pressure and vascular resistance
during a prolonged wakefulness-sleep cycle, while need to be clarified. This has never been investigated
monitoring the electroencephalographic patterns. An- in humans except in a grossly qualitative way (123,
giotensin was injected repeatedly. In nine subjects the 259). Note that carotid baroreceptor stimulation has
sensitivity of the baroreflex was greater during sleep similar hypotensive effects in sleeping and awake dogs
than during wakefulness, and in seven subjects the (332). In contrast the pressor and tachycardic effects
difference was significant. The increased baroreflex of carotid baroreceptor inhibition in cats have been
sensitivity occurred during slow-wave sleep, but it was found to be markedly reduced during sleep (16).
particularly evident during rapid-eye-movement sleep Recent studies have suggested that baroreflex sen-
(84).Indeed in two subjects this was the only condit,ion sitivity may also be related to circadian rhythms (156).
in which an increased sensitivity could be observed. In normal subjects 5-min infusions of progressively
The increase in baroreflex sensitivity was inversely increasing doses of norepinephrine were performed at
related to the hypotension caused by sleep. However, 3-h intervals during a 24-h period. The steady-state
the fall in pressure per se was not responsible for the changes in heart rate obtained during each infusion
alteration of the reflex (by displacing the drug-induced were related to the increases in blood pressure (indi-
baroreceptor stimuli toward a more sensitive portion rect measurements) to evaluate the sensitivity of the
of the stimulus-response curve), because the increased baroreceptor-heart rate reflex a t each 3-h interval. In
baroreflex sensitivity persisted when, with the subjects each subject maximal sensitivities were observed at 3
asleep, blood pressure was raised back to presleep P.M. and at 12 P.M., times during which minimal in-
values by angiotensin infusion. In some subjects the creases in blood pressure with the drug infusions were
increased baroreflex sensitivity was inversely related also observed. These findings may have a bearing on
to the bradycardia caused by sleep. In others, however, the change in sensitivity of the baroreceptor-heart
this relationship was negligible. Thus the increased rate reflex during sleep. More importantly, however,
sensitivity of the reflex during sleep could not be they suggest the possibility that baroreceptor control
explained by a simple reduction in base-line heart rate. of heart rate (and perhaps of blood pressure) under-
The variations in baroreflex sensitivity observed goes a circadian rhythm, in analogy with other he-
throughout wakefulness and sleep in one subject are modynamic variables (234, 253, 327). Incidentally this
shown in Figure 19. provides an experimental basis for the methodological
In a later study the same group reported further caution of comparing reflex function within and among
evidence on this topic (54). In a larger number of subjects by performing the studies during the same
observations the increased sensitivity of the barore- period of the day.

SLOPE O F 2 9
eAnonCCEPlOR
RESPONSE 2 0
16
2Joo 2~00 om om 0300
TIME
Anesthesia
Anesthesia diminishes the ability of arterial baro-
receptors to induce a vagally mediated bradycardia.
Bristow et al. (56) reached this conclusion about sub-
jects studied before and after induction of anesthesia.
Vagolytic agents commonly used in the preanesthetic
period were avoided, and the subjects were breathing
spontaneously. Average reflex sensitivity (calculated
by the slope relating the lengthening in R-R interval
to the increase in systolic pressure induced by phen-
ylephrine) was 9.7 ms/mmHg in the control condition.
During anesthesia the sensitivity was reduced to 6.5
ms/mmHg. The reduction was similar when barbitu-
rates or nitrous oxide combined with halothane were
used. The reduction was not related to changes in
base-line blood pressure and was observed when base-
line heart rates were either increased (thiopental) or
decreased (nitrous oxide and halothane) by the anes-
thetic. Thus the anesthetic state per se was responsible
for the reduction in the baroreflex sensitivity presum-
ably by interfering with the central integrating mech-
anism of the reflex (178) or with the vagal influence
on the heart (137). Others have reached similar con-
clusions (89).
CHAPTER 2 0 ARTERIAL BAROREFLEXES 777
FIG. 19. Changes in sensitivity
of baroreceptor-heart rate reflex
during wakefulness-sleep cycle in
1 subject. Sensitivity calculated
from slope of increase in R-R in-
terval in response to systolic pres-
sure rise induced by andotensin
injections. Arrows, times of injec-
tion; 0, slopes. Diagram shows
systolic, diastolic, and sometimes
mean blood pressure (0) values.
Bottom, electroencephalogram
(EEG) patterns: greatest level,
wakefulness (W); lowest level,
rapid-eye-movement (REM)
sleep; and intermediate levels,
slow-sleep stages (I, 11, 111, IV).
[From Smyth et al. (307), by per-
mission of the American Heart
Association, Inc.]
OLOO 0500 0600 0700
There are no data on the effects of anesthesia on
arterial baroreceptor control of vascular resistance and
blood pressure in humans. The reports that under
anesthesia carotid sinus nerve stimulation or lidocaine
infiltration causes alterations in blood pressure and
peripheral blood flows merely provide qualitative evi-
dence for a function of this reflex under this condition.
In dogs electrical stimulation of the carotid sinus
nerves caused similar blood pressure reductions before
and during anesthesia. However, the reductions were
slower to develop and to disappear during anesthesia
(332). Reduced pressor responses to common carotid
occlusion have also been observed in dogs with a
variety of anesthetic agents (76). If these findings were
to be confirmed in humans, they would imply a reduc-
tion in homeostatic blood pressure regulation under
anesthesia.
Central Blood Volume and Posture
An aspect of arterial baroreceptor control of circu-
lation that has recently emerged from animal studies
is its modulation by reflexes originating in cardiopul-
monary receptors with vagal afferent pathways. It has
been shown that normally these receptors counteract
778 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM 111
some of the baroreceptor influence on the cardiovas-
cular system and that this effect progressively in-
creases when central blood volume and cardiopulmo-
nary receptor activity is increased (65, 177, 208, 219,
220).
BevegHrd et al. (35, 37) have examined in normal
subjects the effects of carotid baroreceptor stimulation
by neck suction during control conditions and during
a reduction in central venous pressure by 47%-68%
through application of lower-body suction (-40
mmHg). The bradycardic response to baroreceptor
stimulation was not different in the two conditions.
On the other hand the hypotension and the reduction
in total peripheral resistance induced by the stimula-
tion were significantly greater during the lower-body
suction than before it. This suggested that a reduction
in the activity of the cardiopulmonary receptors (pro-
duced by the fall in central venous pressure) had
increased the circulatory influence exerted by the ar-
terial baroreceptors but that this increase had oc-
curred through the vascular component of this influ-
ence with no effect on the cardiac component. This
concept has recently been extended in studies indicat-
ing that the forearm vasoconstrictor response to inhi-
bition of carotid baroreceptors (neck pressure) is aug-
mented by mild lower-body suction (A. L. Mark, un-
published observations). This augmentation was
greater than the sum of the separate responses to neck
pressure and lower-body suction.
Takeshita et al. (311) have examined in normal
subjects the effects of physiological alterations in the
activity of cardiopulmonary receptors on the arterial
baroreceptor control of heart rate. In this study baro-
receptors were stimulated either globally by phenyl-
ephrine injections or selectively at the carotid sinuses
(neck suction). The reflex reductions in heart rate
were evaluated within a range of central venous pres-
FIG. 20. A: prolongation of pulse interval caused
by neck suction in 8 supine subjects before ( 0 ) and
after (A) propranolol. B: responses of 5 standing sub-
jects before ( 0 )and after (A) propranolol. [From Eck-
berg, Abboud, and Mark (99).]
sures from 1 mmHg to 9 mmHg obtained by reducing
or increasing venous return through moderate lower-
body suction (-20 mmHg) or leg elevation, respec-
tively. With these interventions reflexes from the car-
diopulmonary receptors were engaged, because there
were marked vasomotor changes in the forearm in
absence of any alteration in heart rate and systolic
blood pressure. This engagement, however, did not
modulate the baroreceptor-heart rate reflex because
the bradycardic responses to baroreceptor stimulation
were identical throughout. Takeshita et al. (311) there-
fore agreed with Beveghrd et al. (37) on the inability
of the cardiopulmonary receptors to affect barorecep-
tor-heart rate control in humans.
Thus the evidence suggests that in humans physio-
logical alterations of cardiopulmonary baroreceptor
activity modulate arterial baroreflex control of vascu-
lar resistance but not heart rate. This interaction is
discussed in greater detail in the chapter on cardio-
pulmonary baroreflexes by Mark and Mancia in this
Handbook.
Interaction between these two reflexogenic areas
has a special importance in humans because of the
natural simultaneous engagement of these reflexes
during orthostatic stress. In apparent agreement with
the findings we have mentioned, stimulation of arterial
baroreceptors did not cause greater changes in R-R
interval in the upright than in the prone position (102,
257, 258). In the former condition, however, sympa-
thetic influences on the sinus node increase with an
increase in heart rate and possibly with a reduction of
the cholinergic effects (99, 258, 311). When this factor
was removed by P-adrenergic receptor blockade, R-R
interval responses to carotid baroreceptor stimulation
were found to be greater when in an upright position
[Fig. 20; (99)l. Because of the evidence discussed
above, reduction in activity of the cardiopulmonary
A Supine 8 Stond ing
r n=8
}I SE
-
'.Ot
0.8-
-0 - co.00 I
>
0-6- .ooI
-
2 -
a
a1 0 . 4 -
-
0 -
0.2 -
t t
"0 -20 -40 -60 0 -20 -40 -60
Neck Chomber Pressure, mmHg
 CHAPTER 20: ARTERIAL BAROREFLEXES 779

receptors cannot be held responsible for this aug-

mented response and other mechanisms must be
sought.
RR r = 0.91
Imsecl a
PATHOLOGICAL STATES
Slope= 27.3

Hypertension
HEART RATE. Bristow et al. (55) and Gribbin et al. 1200
(138) demonstrated that baroreceptor control is al-
tered in human hypertension. In their study the
lengthening in R-R interval that accompanied the
increase in systolic blood pressure induced by phen-
ylephrine (i.e., the ramp method) was compared in
normal subjects and in subjects with essential hyper-
tension (Fig. 21). In normal subjects the lengthening
in R-R interval averaged -13 ms/mmHg rise of sys-
tolic pressure. In hypertensive subjects the lengthen-
ing was progressively reduced from mild to severe
hypertension. The observations by Bristow et al. have 1000
been confirmed and extended (264, 302, 303, 345). It
was shown that 1) lengthening in R-R interval that
followed arterial baroreceptor stimulation was reduced
in secondary as well as in primary hypertension (255);
2) reduction could be seen in subjects with borderline
hypertension, at least if their pressure was in the upper
range that defines this condition (97, 138, 164, 312,

*/
313); and 3) shortening in R-R interval that accom-
panied baroreceptor deactivation (trinitroglycerin in-
jection) was also reduced in hypertension. Reduced R-
R interval responses to baroreceptor deactivation in 8 00
.I s *
hypertension have also been found with the steady- 1

state method. Korner et al. (184) reported these re-
ductions to be somewhat less marked than with the
ramp method (see Fig. 16). However, Mancia et al.
(218) observed that when base-line blood pressure was
-40 mmHg above normal these responses were sub-
stantially reduced. It can therefore be concluded that
the sensitivity of the arterial baroreceptor control of
the sinus node is impaired in human hypertension and
that this is evident along the whole stimulus-response
curve of this reflex function. In addition, since the
elevated blood pressure in hypertensives is not accom-
panied by a reduction in base-line heart rate, it can be
concluded that there is a resetting of the baroreflex
toward the high pressure.
Mancia et al. (218) compared in hypertensive sub-
jects the heart rate changes induced by stimulation
and deactivation of all arterial baroreceptors (drug
technique) and by stimulation and deactivation of
only carotid baroreceptors (neck chamber). A similar
comparison in normotensive subjects showed much
greater heart rate changes in the former condition,
suggesting an important reflex control of heart rate by
the aortic baroreceptors (214). In hypertensive sub-
jects, however, the heart rate changes obtained with
the two techniques, in addition to being reduced, were
almost indistinguishable. These findings suggest that
in hypertension aortic baroreflexes may be markedly
impaired and that any residual reflex heart rate con-
110 120 130
A SYSTOLIC PRESSURE
r = 0.73
Slope = 1.4
. ..
B 170 180 190 200
SYSTOLIC PRESSURE
FIG. 21. Slope of linear regression (lines) between increases in
systolic pressure (mmHg) induced by angiotensin and resulting
lengthening of R-R interval. Data from normal subject ( A ) and
hypertensive subject ( B ) .[From Bristow et al. (55),by permission
of the American Heart Association, Inc.]
trol may stem predominantly from the carotid sinus
area. Interestingly a greater reduction of aortic than
carotid baroreflexes has recently been observed in
spontaneously hypertensive rats ( 163).
ARTERIAL BLOOD PRESSURE. There have been a few
studies on carotid baroreceptor control of blood pres-
sure in human hypertension.
Mancia et al. (218) examined in moderate and severe
essential hypertension the blood pressure effects of
increasing carotid transmural pressure to 20-25 mmHg
780 HANDBOOK O F PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11

mmHg than in normotensive subjects. Such resetting may be

1 induced by central influences on the reflex arc (183).
5 W ,601 A simpler explanation, however, is that the progressive
stiffening of the arterial walls that occurs in this dis-
cn ease (17, 346) progressively reduces the ability of ele-
cn
w vated pressure levels to provide an effective barore-
ceptor stimulus.
-I In the study by Mancia et al. (218) the maximal
5 120- baroreflex sensitivity in severe hypertension (obtained
a for baroreceptor stimulation) was only slightly re-
w
+ duced compared with the maximal baroreflex sensitiv-
a
a ity in normotensive subjects (obtained for barorecep-
z l tor deactivation). These investigators therefore sug-
gested that the effectiveness of arterial baroreceptor
control of blood pressure may be preserved better in
I hypertension than the effectiveness of heart rate con-
I I I I I
80 120 1 6 0 mmHg trol (213). Because in hypertension, as in normoten-
sion, carotid baroreceptor control of blood pressure
CAROTID TRANSMURAL P R E S S U R E largely depends on modulation of vascular resistance

FIG. 22. Carotid baroreceptor influence on blood pressure in 11

(34, 38, 213, 325), there may be less impairment of
normotensive (o),18 moderately hypertensive (o), 17 severely hy- arterial baroreceptor control of vascular resistance
pertensive (x) subjects & SE for mean arterial pressure during than of heart rate. Currently, however, no definite
control period in each group, respectively. Solid line represents conclusion can be reached on this point. In humans
mean of individual regression coefficients relating mean arterial Wagner et al. (337) and BevegHd et al. (34) found
pressure to increased and decreased carotid transmural pressure
with respect to control values; dashed lines indicate standard errors similar blood pressure responses to carotid barorecep-
of regressions. Data are shown for steady-state effects of neck tor stimulation by neck suction in normotensive and
chamber, with carotid transmural pressure calculated as difference hypertensive subjects. However, in a recent study in
between mean arterial pressure and tissue pressure outside carotid which sinusoidal rather than sustained neck suction
sinuses. Latter was calculated from variation in value of neck
chamber pressure after application of correction factors for loss of
was used, Beveghrd et al. (36) observed reduced re-
pressure transmission through neck tissues. [From Mancia et al. sponses in hypertension. Preservation of blood pres-
(218). by permission of the American Heart Association, Inc.] sure and of vascular effects elicited from isolated ca-
rotid sinuses has been observed in hypertensive rats
above the existing level and of decreasing carotid and rabbits (12, 246); in contrast the heart rate re-
transmural pressure to 20-25 mmHg below the existing sponses are impaired (11). Note that hypertrophy of
level. Baroreflex sensitivity was evaluated separately the vessel wall amplifies the changes in resistance that
in the two conditions by the coefficient of the linear occur in response to smooth muscle contraction or
relationship between carotid transmural pressure and relaxation (118), whereas cardiac hypertrophy seems
mean arterial pressure changes. As shown in Figure to be accompanied by less ability of the sinus node to
22, for reductions in carotid transmural pressure (i.e., respond to neural stimuli (101).
for baroreceptor deactivation), baroreflex sensitivity Thus differences in effects of hypertension on
for blood pressure was progressively less in moderate baroreflex control of heart rate and blood pressure
and severe hypertension than in a control group of could relate partly to differences in effects of hyper-
normotensive subjects. On the other hand, for in- tension on responsiveness of the sinus node and blood
creased carotid transmural pressure (i.e., for baro- vessels (213). Alternatively the dissociation of effects
receptor stimulation), average baroreflex sensitivity of hypertension on baroreflex control of heart rate, as
was progressively greater in modest and severe hyper- opposed to blood pressure and vascular resistance,
tension than in the normotensive subjects. Thus the may reflect differences in baroreflex control of para-
normal asymmetry of the baroreflex was abolished in sympathetic and sympathetic activity. Baroreflex con-
moderate hypertension and reversed in severe hyper- trol of heart rate primarily involves parasympathetic
tension in which the blood pressure response was mechanisms, whereas control of vascular resistance
much larger for baroreceptor stimulation than for mainly reflects sympathetic activity. Accordingly,
deactivation. These findings suggest that the set point greater impairment of baroreflex control of parasym-
of the carotid baroreceptor-blood pressure reflex is pathetic than of sympathetic activity produced by
displaced by hypertension from near saturation to hypertension could account for impairment in heart
positions closer and closer to the threshold of the rate control and preservation of vascular and blood
stimulus-response curve. In other words they suggest pressure control. This differential effect of hyperten-
the existence of a very marked resetting phenomenon sion on parasympathetic and sympathetic mechanisms
that may make the tonic blood pressure influence of has recently been observed in renal hypertensive rab-
this reflex “paradoxically” smaller in hypertensive bits (140). The dissociation of baroreflex control of
 CHAPTER 20: ARTERIAL BAROREFLEXES 78 1

parasympathetic and sympathetic activity in hyper- study by Eckberg et al. (101) the bradycardic effect of
tension may involve central neural as well as afferent baroreceptor stimulation was equally depressed in
mechanisms. subjects with or without heart failure. Thus heart
failure and sodium and water retention are not nec-
ARTERIAL BAROREFLEXES AS CAUSE OF ESSENTIAL HY-
essary or sole conditions for reduced baroreceptor-
PERTENSION. A time-honored hypothesis is that a de-
heart rate control in patients with heart disease.
rangement of arterial baroreflex function may contrib- 2. An increase in central venous pressure in cardiac
ute to the development of essential hypertension (174).
patients may stimulate cardiopulmonary receptors,
There is little evidence for or against this hypothesis and this may reduce the extent of the baroreceptor
in humans. Sleight (304) reported that bilateral dener- influence on heart rate. This possibility was recently
vation of the carotid sinus in one normotensive subject supported by Net0 et al. (242), who have shown that
was followed by development first of labile hyperten- the reduced sensitivity of the baroreceptor-heart rate
sion and then in several years by an established hy- reflex (phenylephrine injection) in subjects with heart
pertensive state. This might have been coincidental, failure was clearly improved after treatment with ni-
however, since indeed the hypertension that follows troglycerin, which increased cardiac output and re-
surgical denervation of the carotid sinuses in humans duced central venous pressure. On the other hand
has been reported to subside within hours or days (54, treatment with hydralazine, which increased cardiac
59, 155, 266, 349). These observations are not conclu- output but did not reduce central venous pressure,
sive,however, because normalization of blood pressure
had no effect on the sensitivity of the baroreflex.
might be caused by compensatory buffering from aor- However, the observation that a marked reduction in
tic or other extracarotid reflexogenic areas of cardio-
baroreflex sensitivity can occur in cardiac patients
vascular control. There is conflicting evidence as to
with no heart failure suggests that an increase in
whether complete artelial baroreceptor denervation
central venous pressure is also not a necessary or sole
produces long-lasting hypertension in animals (62, 72, mechanism. Moreover, there are data in animals show-
116, 158, 239).
ing that cardiac receptors are impaired under condi-
Although a primary role of arterial baroreflexes in tions of chronic overload (136, 359). The evidence so
causing hypertension is debatable, there can be little far available in humans does not support the view that
doubt about their participation as a secondary phe- cardiopulmonary receptors serve as an important
nomenon. The resetting of reflexes that occurs in this
modulator of the baroreceptor-heart rate reflex.
disease should actively defend and thus contribute to 3. The most important factor in the decreased
maintenance of the elevated blood pressure levels. baroreflex control of heart rate in patients with cardiac
disease may relate to the effector site of the reflex arc.
Heart Disease Destruction of intrathoracic nerve plexuses is a rec-
A number of studies have shown that heart disease ognized event with Chagas disease (223, 235). In ad-
is associated with a striking reduction in arterial dition, reduction in sympathetic cardiac effects occurs
baroreceptor control of heart rate. Armorim et al. (15) in patients with cardiac hypertrophy of varying etiol-
reported that baroreflex control of heart rate is im- ogy probably because of reduction in cardiac stores of
paired in patients with Chagas disease, and Eckberg norepinephrine and/or dysfunction in sympathetic
et al. (101) and Goldstein et al. (133) reported similar nerve terminals (66, 67, 74, 286). Vagal cardiac effect
observations in patients with a variety of other cardiac may also be involved, because early in heart disease
diseases (e.g., ischemic, rheumatic, congenital). Eck- there is less tachycardia when vagal tone is abolished
berg et al. (101) showed that with baroreceptor stim- by atropine (15,78,101,133,162).Thus impairment in
ulation produced by phenylephrine, the sensitivity of baroreflex control of heart rate may relate largely to
the baroreceptor-heart rate reflex was reduced by 77% abnormalities in neuroeffector mechanisms.
in cardiac patients. Goldstein et al. (133) reported that Is impairment of the arterial baroreceptor-heart
the tachycardic response to baroreceptor deactivation rate reflex in heart disease paralleled by impairment
caused by tilting or by nitroglycerin infusion was re- of vascular baroreceptor control? There is no evidence
duced in cardiac patients. for this in humans, but some autonomic vascular influ-
The mechanisms that produce marked impairment ences are preserved in heart disease (186, 287). In
of reflex control of heart rate have been the subject of conscious dogs with experimentally induced heart fail-
speculation, and three factors have been proposed. ure, however, the vascular (as well as cardiac) effects
1. This impairment is established at the barorecep- of common carotid occlusion are reduced (154).
tor level, because increased water content and stiffness
of the arterial walls may accompany salt and water
retention during heart failure (360). In the study by Carotid Sinus Syndrome
Goldstein et al. (133), however, the tachycardic re- In some patients, slight compression of one carotid
sponse to tilting was reduced in subjects with normal sinus for several seconds induces striking cardiovas-
cardiac pressures who belonged to functional class I cular changes. These may consist of bradycardia, a
or I1 of the American Heart Association, and in the few seconds of asystole due to sinus arrest or atrioven-
782 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11
tricular blockade, and in some instances a fall in
systolic blood pressure greater than 50 mmHg (120,
148, 326, 342, 349). This condition reflects hypersen-
sitivity of the carotid baroreflex that may remain
asymptomatic or may be associated with episodes of
reduced cerebral perfusion and syncope. There is an
association between carotid sinus hypersensitivity and
older age, extensive atherosclerotic lesions, ischemic
heart disease, and digitalis intoxication (201, 240, 316,
342, 348). A similar condition has also been reported
to occur frequently in subjects with the arteritis known
as Takayasu’s disease (282, 329).
Some considerations on the carotid sinus hypersen-
sitivity syndrome may be relevant to a chapter mainly
devoted to reflex control in physiological states. The
first consideration is the mechanisms. Factors such as
anomalous cardiac responses to neural influences and
central derangements have been studied because de-
nervation or inactivation of the carotid sinuses is not
invariably followed by disappearance of the symptoms
(201, 301, 306). The most likely explanation, however,
is that the origin of this syndrome depends on the
carotid sinus baroreceptors themselves. There is no
evidence for a true hypersensitivity of the receptors,
whereas there is circumstantial evidence for exagger-
ated stimulation by traction from rigid and deformed
carotid and pericarotid tissues. Interestingly, in sub-
jects with Takayasu’s disease and symptoms referable
to a hypersensitive carotid sinus, baroreflex sensitivity
to increased arterial blood pressure with phenyleph-
rine was diminished by 63% (314). Thus mechanical
hyperstimulation may in fact be accompanied by a
markedly reduced baroreceptor responsiveness to
physiological stimuli, possibly because arterial pres-
sure is poorly transmitted through a rigid vascular
mass to the adventitia where the receptors are located
(6). Another interesting point is that, although nor-
mally episodic, the mechanical hyperstimulation of
the baroreceptors may occasionally have a pronounced
tonic component. This is indicated by the marked and
even fatal hypertensive crises that may follow surgical
denervation of a hypersensitive carotid sinus (121,266,
348).
The remaining two considerations are on the pat-
tern and the extent of the hemodynamic influence of
hypersensitive carotid sinuses. The pattern does not
appear to be abnormal. For example, the marked
depressor effect does not involve active vasodilation
mediated by sympathetic cholinergic fibers because it
survives the administration of atropine (152, 201, 342,
349). The extent of the cardiovascular alterations that
occur in this condition (despite the opposition of all
other baroreceptor mechanisms) may be analogous
to the pronounced and long-lasting depressor and
bradycardic effects obtained by Douglas (87, 88) in
rabbits with stimulation of nonmyelinated fibers in
the aortic nerve. Perhaps mechanical activation of this
fiber type plays a role in the production of this syn-
drome.
Other Pathological Conditions
Arterial baroreceptor control of circulation is re-
duced in all pathological conditions with damage to
one or more elements of the reflex arc (i.e., afferent
fibers, centers, and efferent autonomic paths).
Damage to the efferent path explains reduced
baroreflex effectiveness in subjects with diabetes mel-
litus who have a secondary dysautonomic syndrome.
It has been shown that stimulation of arterial baro-
receptors in these subjects by a Valsalva maneuver, or
more selectively by phenylephrine, lengthens the R-R
interval much less than in normal subjects. Indeed, in
patients with the classic syndrome, the response may
be abolished (27, 29, 294). The shortening of the R-R
interval that accompanies baroreceptor deactivation
is also impaired in diabetic subjects with secondary
dysautonomia (110, lll), as is their reflex vascular
control. Lower-body suction in these subjects induces
hypotension at lower suction levels than in normal
subjects, and the forearm vasoconstriction that nor-
mally accompanies this maneuver is attenuated (28).
However, the peripheral reflex responses may be nor-
mal when the heart rate responses are reduced. This
may reflect the early and pronounced vagal dysfunc-
tion that characterizes the condition (344). Damage to
the efferent portion of the reflex arc also contributes
substantially to reduced baroreflex effectiveness in
primary dysautonomias (19,157,251,335).It probably
also explains the reduced heart rate control of the
arterial baroreceptors found in renal failure, independ-
ent of the preceding or concomitant effects of hyper-
tension on the reflex (190, 197, 255, 322).
Heart rate changes induced by the Valsalva maneu-
ver are frequently abolished in the acute and chronic
phases that follow cerebrovascular accidents (14), and
the changes are reduced in subjects with tabes dorsalis
(293) and other neurological conditions (20, 294), pre-
sumably because of damage to afferent, efferent, or
integrating structures of the baroreflex within the
brain. Central deafferentation of the baroreceptor sig-
nal has been proposed as an explanation for the hy-
pertension frequently observed in bulbar but not in
other types of poliomyelitis (18, 228).
Selective damage to afferent baroreceptor fibers at
a central level is believed to be the cause of impairment
of cardiovascular control in some dysautonomic syn-
dromes, because engagement of efferent autonomic
pathways by central or other afferent influences yields
normal cardiovascular responses (19,196).Impairment
of the baroreceptor signal has been described in neu-
ralgia of the glossopharyngeal nerve (271)) and Kezdi
(169) found evidence that this may explain the hyper-
tension that sometimes accompanies the polyneuritic
form of idiopathic porphyria. In one such case anes-
thetic blockade of the carotid sinus nerves was indeed
followed by no increase in blood pressure and heart
rate, suggesting the absence of the normal tonic inhib-
itory influence originating from this reflexogenic area.

A similar explanation has been suggested for hyper-
tension in other diseases characterized by polyneuritis
(188,233).
MODIFICATION OF ARTERIAL
BAROREFLEXES BY DRUGS
p-Adrenergic Antagonists
Pickering et al. (258) observed that intravenous
injection of 10 mg of propranolol in normal subjects
was followed by an augmentation in the slope of the
relationship between the lengthening of R-R interval
and the “ramp” blood pressure rise induced by phen-
ylephrine. With one exception (302), this observation
has been confirmed and extended in subsequent stud-
ies. The increase in R-R interval after baroreceptor
stimulation is indeed much larger after intravenous
administration of P-adrenergic receptor antagonists,
and this occurs either when the stimulus is applied to
all baroreceptors or to only carotid baroreceptors (94,
99, 102, 311). The potentiation of the baroreceptor-
heart rate response is evident in the supine or standing
position and during exercise (99, 102). The potentia-
tion has also been observed at decreased or increased
central venous pressure (311). Finally, augmentation
of the baroreceptor-heart rate reflex after P-receptor
blockade is not limited to normal subjects but includes
borderline hypertensive subjects despite the impair-
ment of baroreflex function that characterizes this
disease (313). Thus it can be concluded that choliner-
gic baroreceptor influences on the sinus node are
invariably greater after acute blockade of P-adrenergic
receptors and that activation of these receptors nor-
mally exerts an opposing action on the sensitivity of
the reflex control. Figure 20 shows an example of the
increased baroreceptor effect on the sinus node after
P-adrenergic receptor blockade.
The mechanisms by which such action is exerted
have not been entirely clarified. The most credible
hypothesis is that sympathetic effects limit the extent
of cholinergic effects on the sinus node and that this
limitation occurs even at the low-normal level of sym-
pathetic tone. There is some evidence for this type of
sympathetic influence in animals (126, 127, 275). We
discussed earlier that this may be one of the mecha-
nisms responsible for the direct relationship that exists
between base-line R-R intervals and sensitivity of
baroreceptor-heart rate control and for the progres-
sive attenuation of baroreflex control of heart rate
during exercise. Other explanations, however, should
not be overlooked. Activation of P-receptors may op-
pose baroreceptor-heart rate control a t a central level
(86) and may counteract this reflex on afferent as well
as on efferent sites of the reflex arc. There is evidence
in animals that the firing rate of arterial baroreceptors
within a given pressure range is increased after pro-
pranolol (9, 122).
CHAPTER 20: ARTERIAL BAROREFLEXES 783
An interesting question regarding the potentiation
of the arterial baroreflex by P-adrenolytic drugs is the
possibility that such potentiation may partly explain
the antihypertensive action of these drugs. Currently,
however, this possibility is not supported by experi-
mental evidence. In two studies on hypertensive pa-
tients in which effects of arterial baroreceptor stimu-
lation on R-R interval were examined (DhenvleDhrine
.& I A
injections) before and after weeks of continuous treat-
ment with P-adrenolytic agents, no difference in the
sensitivity of the baroreflex was found, although ar-
terial blood pressure had often been reduced (302). In
a third, similar study (345) the baroreceptor-heart
rate reflex was more sensitive during administration
of P-blocking drugs. The increased sensitivity, how-
ever, could not be related to the hypotensive effect of
the drug in specific patients. If the potentiation of the
baroreceptor-heart rate control induced by P-blocking
drugs mainly derives from the vagal-sympathetic in-
teraction at the sinus node, there may be little reason
to expect that a similar potentiation would involve
baroreceptor vascular and blood pressure control.
Cardiac Glycosides
In animals the arterial baroreceptor activity within
physiological pressure ranges increases after digitalis
administration (229, 263), as do hemodynamic re-
sponses to common carotid occlusion (262, 269). In
conscious dogs the bradycardic effect of digitalis is
much less evident after section of the sinoaortic nerves
(231).
In humans the indirect evidence for modification of
reflex cardiovascular control by digitalis was reported
by Mason and Braunwald (225). In their study, admin-
istration of 0.5-0.6 mg of ouabain induced constriction
of forearm resistance vessels in normal subjects,
whereas the same dose induced dilation of these ves-
sels in subjects with heart failure. Evidence for an
effect of digitalis on arterial baroreflexes was provided
by two subsequent studies in which bradycardic re-
sponses to arterial baroreceptor stimulation by phen-
ylephrine were augmented after administration of car-
diac glycosides (69, 317), although in one study the
increase was not significant (317).
A more complete analysis of the effects of digitalis
on arterial baroreflexes has recently been made by
Ferrari et al. (115).Subjects with no heart failure were
selected in order to examine the effects of digitalis on
baroreflexes in the absence of base-line changes in
pulse pressure (and thus in baroreceptor stimuli)
brought about by the inotropic actions of the drug.
The results are shown in Figures 23 and 24. Arterial
baroreceptor stimulation by phenylephrine caused an
average lengthening of 8.1 ms/mmHg increase in sys-
tolic blood pressure in the control condition. After
intravenous injection of 0.8 mg of lanatoside C, the
lengthening averaged 11.8 ms/mmHg increase in sys-
tolic pressure. The augmentation in the response was
784 HANDBOOK OF PHYSIOLOGY - THE CARDIOVASCULAR SYSTEM I11

statistically significant, was observed in 16 of 18 sub- arterial pressure obtained with carotid baroreceptor
jects, and occurred to a similar extent in subjects with stimulation (neck suction) were also significantly
either high or low base-line baroreflex sensitivity. The greater after lanatoside C. There was no correlation
increase in R-R interval and the reduction in mean between the extent of the digitalis-induced potentia-
tion of the baroreflex and the base-line bradycardia
caused by the drug. Furthermore the responses to
PHENYLEPHRINE TRINITROGLYCERINE
baroreceptor stimulation were potentiated selectively.
n= 18 n= 2 0 In the same subjects, inhibition of arterial barorecep-
+msec/+mm~g -msec/-mmHg
tors caused reductions in R-R interval and increases
14-
in pressure that were not significantly different before
1 and after digitalis. These results support several con-
12-
clusions: 1 ) digitalis affects arterial baroreflexes in
10- humans at clinical doses; 2 ) the effect consists of a
potentiation of the heart rate and blood pressure re-
8-
sponses to baroreceptor stimulation, which implies
6-
potentiation of both the vagal and the sympathetic
I
components of the reflex; and 3 ) this phenomenon can
involve normal and impaired baroreflexes.
The potentiation of the baroreflexes induced by
digitalis may be largely explained by the action of this
drug on the baroreceptors themselves (263,283). This
control digitalis potentiation should favor the reduction in autonomic
FIG. 23. Sensitivity of baroreceptor-heart rate reflex during ar- cardiac and vascular excitation that occurs with digi-
terial baroreceptor stimulation by phenylephrine and arterial talis. However, the results of Ferrari et al. (115)suggest
baroreceptor deactivation by trinitroglycerin before and after intra- that the practical consequences of the effects of digi-
venous administration of 0.8 mg lanatoside C. Sensitivity expressed talis on arterial baroreflexesmay be difficult to predict.
by regression coefficient of relationship between changes in R-R
interval (ms) and changes in systolic arterial pressure. Data are The potentiation does not occur along the whole stim-
means f SE. [From Ferrari et al. (115), by permission of the ulus-response curve of the baroreflex but only in the
American Heart Association, Inc.] portion of the curve above the set point.

-I < 0.05

-Z+lOO-
w \
w
(3 0
0°
I ’\
\
0 \
z
z a 0 -
a
I
FIG. 24. Changes in mean arterial pressure (MAP) 0 -2 0 -
and R-R interval (HI) induced by carotid baroreceptor
r I -100- r 1
 CHAPTER 20: ARTERIAL BAROREFLEXES 785

Antihypertensive Drugs previous drugs, abolished the heart rate effects and
greatly impaired the blood pressure effects of the
In a series of studies Mancia et al. (209, 210, 215) carotid baroreflex.
examined the modification of the carotid baroreflex These results suggest that the sensitivity of the
that accompanied antihypertensive treatment with carotid baroreceptor control of circulation is not ap-
several drugs. The depressor responses to stimulation preciably altered by antihypertensive drugs adminis-
of the carotid baroreceptors and the pressor responses tered at effective doses and for relatively prolonged
to inhibition of the carotid baroreceptors (with neck periods. This does not imply absence of any effect on
chambers) were virtually identical before and after different components of the reflex arc. In animals
intravenous injection of 150 pg and 300 pg of clonidine, arterial baroreceptor activity increases after clonidine
although these doses induced a fall in base-line mean (1, 179) and prazosin (61) probably because of a re-
arterial pressure (215). The responses to carotid duction in sympathetic tone and an increased vascular
baroreceptor stimulation and deactivation were also distensibility. It has also been suggested that clonidine
unchanged by a 2-wk administration of prazosin at acts centrally on the baroreflex (144,173,179).If these
hypotensive doses (210).The responses to barorecep- effects occur in humans, however, they appear to be
tor inhibition were slightly reduced by prolonged ad- compensated by other alterations that maintain un-
ministration of hypotensive doses of methyldopa, but altered overall reflex function.
the responses to baroreceptor stimulation were unal- When baroreflex function is unaltered at a definitely
tered (209).With all three drugs there were only minor lower base-line blood pressure, resetting of the reflex
changes in the reflex effects of carotid baroreceptor toward a lower pressure range must have occurred.
manipulations on heart rate. On the other hand, ad- During antihypertensive treatment with these agents,
ministration of a ganglion-blocking agent, at doses resetting toward a lower pressure may actively defend
that reduced base-line blood pressure as much as the the antihypertensive effects of the drugs.

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