Am J Physiol Regul Integr Comp Physiol 288: R846 –R855, 2005;
doi:10.1152/ajpregu.00474.2004.
Invited Review
CALL FOR PAPERS
Baroreflex Control of Sodium Excretion and Arterial Pressure
A neural set point for the long-term control of arterial pressure: beyond the
arterial baroreceptor reflex
John W. Osborn, Frédéric Jacob, and Pilar Guzman
Department of Physiology, Lillehei Heart Institute, University of Minnesota, Minneapolis
sympathetic nervous system; hypertension; baroreflex
reflex in long-term
control of arterial pressure has been a topic of considerable
debate and controversy for decades. This debate was initiated
in the 1970s by a series of studies from Cowley and coworkers
demonstrating that sinoaortic denervation (SAD) had no longterm effect on the basal level of arterial pressure in the
conscious dog (20). These findings have since been confirmed
by several laboratories reporting a normal mean level of
arterial pressure after SAD in several species (16, 61, 72).
Cowley et al. (20) went on to show that in several models of
renovascular hypertension in the dog the magnitude of hypertension was not affected by SAD, further supporting the
concept that arterial baroreceptors are incapable of chronically
buffering hypertensive stimuli (18, 19, 21). Consistent with
this view, we reported that SAD does not alter the steady-state
level of hypertension in a genetic model of human essential
hypertension, that is, the spontaneously hypertensive rat (63).
THE ROLE OF THE ARTERIAL BARORECEPTOR
Address for reprint requests and other correspondence: John W. Osborn,
Univ. of Minnesota, Dept. of Physiology, 6 –125 Jackson Hall, 321 Church St.,
Minneapolis, MN 55455 (E-mail: [email protected]).
R846
These observations, combined with the knowledge that arterial
baroreceptors reset to sustained changes in arterial pressure (5,
57), led to the concept that the arterial baroreceptor reflex is
incapable of long-term control of arterial pressure (17, 34).
However, three papers published over the past three years
have sparked renewed interest in this topic and refueled the
debate. In each of these studies, the responses of either arterial
pressure or renal sympathetic nerve activity to a 7-day stimulus
were examined in conscious animals, and the results were
consistent with sustained baroreflex control of the cardiovascular system. In 2002, Thrasher (78) described an alternative
surgical method for chronically decreasing baroreceptor afferent input to the brain and reported sustained hypertension in the
dog (78). The following year, Barrret and colleagues (7)
demonstrated in conscious rabbits a marked reduction in renal
sympathetic nerve activity in response to hypertension produced by 7 days of intravenous infusion of ANG II. Then, in
2004, Lohmeier et al. (55) reported that chronic electrical
stimulation of the carotid sinus in dogs produces a sustained
decrease in arterial pressure (55). These studies and their
relevance to arterial baroreceptors and long-term control of
arterial pressure are discussed in more detail in companion
articles in this journal.
Further support for a long-term role of arterial baroreceptors
is provided by the studies of Howe and colleagues (38, 39) and
our laboratory (66, 67), demonstrating salt-dependent hypertension in SAD rats, which suggested that baroreceptors chronically buffer this hypertensive stimulus. These studies, in
combination with the three cited above, suggest that the arterial
baroreceptor reflex can impact on long-term control of arterial
pressure under certain conditions.
If the baroreceptor reflex does regulate arterial pressure
chronically, it remains unresolved which peripheral targets of
the sympathetic nervous system are involved in this control
system. Clearly, alteration of sympathetic nerve activity (SNA)
to most vascular beds (e.g., renal, splanchnic, skeletal muscle)
result in acute arterial pressure responses, but the individual
contributions of these targets in the chronic regulation of
pressure still remain unclear. One reason is because over the
past few decades, the primary focus of many studies has been
on neural control of the kidney, as this vascular bed has been
thought to play a major role in long-term control of arterial
pressure. Increases in renal SNA results in several responses
that potentially chronically elevate arterial pressure, including
sodium and water retention, increased activity of the reninangiotensin-aldosterone system, and increased renal vascular
resistance (22). The focus on the kidney has also been driven
by the elegant theoretical framework of Guyton and colleagues
(34, 35). Guyton and colleagues propose that the only mech-
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Osborn, John W., Frédéric Jacob, and Pilar Guzman. A neural
set point for the long-term control of arterial pressure: beyond the
arterial baroreceptor reflex. Am J Physiol Regul Integr Comp Physiol
288: R846 –R855, 2005. doi:10.1152/ajpregu.00474.2004.—Arterial
baroreceptor reflex control of renal sympathetic nerve activity
(RSNA) has been proposed to play a role in long-term control of
arterial pressure. The hypothesis that the “set point” of the acute
RSNA baroreflex curve determines the long-term level of arterial
pressure is presented and challenged. Contrary to the hypothesis,
studies on the long-term effects of sinoaortic denervation (SAD) on
arterial pressure and RSNA, as well as more recent studies of chronic
baroreceptor “unloading” on arterial pressure, suggest that the basal
levels of sympathetic nerve activity and arterial pressure are regulated
independent of arterial baroreceptor input to the brainstem. Studies of
the effect of SAD on the long-term salt sensitivity of arterial pressure
are consistent with a short-term role, rather than a long-term role for
the arterial baroreceptor reflex in regulation of arterial pressure during
changes in dietary salt intake. Renal denervation studies suggest that
renal nerves contribute to maintenance of the basal levels of arterial
pressure. However, evidence that baroreflex control of the kidney
plays a role in the maintenance of arterial pressure during changes in
dietary salt intake is lacking. It is proposed that a “baroreflexindependent” sympathetic control system must exist for the long-term
regulation of sympathetic nerve activity and arterial pressure. The
concept of a central nervous system “set point” for long-term control
of mean arterial pressure (CNS-MAP set point), and its involvement
in the pathogenesis of hypertension, is discussed.
Invited Review
THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
EXTRAPOLATION OF THE ACUTE RSNA BAROREFLEX
CURVE SET POINT TO LONG-TERM CONTROL OF
ARTERIAL PRESSURE: THE HYPOTHESIS
Figure 1 illustrates the central hypothesis to be addressed in
this review. Renal sympathetic nerve activity (RSNA) is under
the tonic control of sympathetic premotor neurons in the rostral
ventrolateral medulla (RVLM) of the brainstem. This level of
RSNA modulates arterial pressure via the known actions of
renal nerves on the kidney, including renin release, tubular
sodium reabsorbtion, and renal vasomotor tone (22). The level
of RSNA is dynamically controlled by input from the aortic
and carotid baroreceptors which, via a series of projections to
the nucleus tractus solitarius and caudal ventrolateral medulla,
inhibit the activity of the RVLM and therefore RSNA (31).
This negative feedback reflex results in the classic arterial
baroreflex curve, in which the set-point determines the steadystate relationship between the basal level of RSNA and arterial
pressure. Finally, this hypothesis assumes that there is a direct
Fig. 1. Schematic illustration of the arterial baroreceptor reflex in long-term
control of arterial pressure. RSNA; renal sympathetic nerve activity. RVLM;
rostral ventrolateral medulla. Dashed line indicates inhibitory pathway.
AJP-Regul Integr Comp Physiol • VOL
relationship between the basal levels of RSNA and arterial
pressure.
The neuroanatomical and neurochemical substrates, as well
as the underlying neurophysiological mechanisms of this pathway have been reviewed elsewhere (31, 69). Many of these
details have been generated by acute studies in anesthetized
animals using various “reductionist” approaches required to
understand the cellular and molecular biology of this reflex
pathway. However, this review will focus primarily on addressing whether this reflex is important in the long-term
control of arterial pressure under physiological conditions.
Therefore, the emphasis will be on studies in which arterial
pressure has been measured over long periods of time in
conscious animals in which the reflex pathway has been stimulated and/or manipulated experimentally. The outcome of
these studies will be reviewed in the context of the following
hypothesis: the long-term level of arterial pressure is determined by the set point of the MAP-RSNA baroreflex curve.
ARTERIAL BAROREFLEX CONTROL OF RSNA IN
LONG-TERM REGULATION OF ARTERIAL PRESSURE
UNDER BASAL CONDITIONS
Alterations in the afferent limb of the reflex: sinoaortic
denervation studies. As soon as it was established that the
baroreceptor reflex arc acts in a classical negative feedback
fashion, it was proposed that denervation of the afferent projections of arterial baroreceptors should result in a sustained
increase in SNA and hypertension secondary to loss of the loss
of sympathoinhibitory input to the brainstem (for a historical
review, see Ref. 68). Although early studies supported this
concept, they were flawed in that arterial pressure was measured acutely under stressful conditions, and therefore the
“hypertension” was an acute stress response rather than a
chronic elevation in arterial pressure. It was not until the
classic studies of Cowley and colleagues (20, 21), utilizing
newly developed 24 h computerized monitoring of arterial
pressure that it was evident that SAD dogs were not hypertensive. These studies were originally interpreted as evidence that
the nervous system was not important in the long-term control
of arterial pressure (33). Rather, it was suggested that the
hypertension after SAD was temporary, and pressure returned
to control levels as a result of pressure natriuresis and diuresis.
Indeed, the normal levels of arterial pressure in SAD dogs have
often been used as an argument for the dominant role of the
kidneys in long-term control of arterial pressure (17, 35).
Subsequent studies over the past 20 years have clearly
demonstrated that failure of SAD animals to remain hypertensive is because the sympathoexcitatory response to SAD is not
sustained chronically. Although relatively few studies have
characterized the time course of changes in arterial pressure
after SAD, most are consistent in that arterial pressure rapidly
increases but slowly returns to normal levels over time. The
rate at which arterial pressure normalizes appears to be species
dependent progressing from ⬃2–3 days in rats (64), to 5–7
days in rabbits (72), to 2–3 wk in dogs (77). A similar study in
nonhuman primates revealed that arterial pressure had not
returned to normal 3 wk after SAD at which time the protocol
ended (73). This species dependence is critical to keep in mind
in the interpretation of studies examining SAD and arterial
baroreceptor “unloading” discussed below.
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anism by which the sympathetic nervous system can chronically regulate arterial pressure is via alterations in the renal
function curve (17, 33). This concept is supported by some
studies demonstrating that renal denervation delays the development of the hypertensive process in some forms of experimental hypertension (40, 48, 49, 81).
The objective of this review is to critically evaluate the
importance of arterial baroreceptor reflex control of the kidney
in long-term control of arterial pressure. The emphasis will be
on regulation of both the basal levels of arterial pressure, as
well as the long-term salt-sensitivity of arterial pressure. Careful analysis of studies to date will suggest that, although the
sympathetic nervous system is important in the chronic control
of arterial pressure, arterial baroreceptors play little to no role
in long-term regulation of the mean level of SNA or arterial
pressure. In addition, although neural control of the kidney
does contribute, in part, to long-term control of arterial pressure, other neural targets (e.g., heart, skeletal muscle, and
splanchnic beds) are also required. This review will conclude
with the hypothesis that a long-term set point for SNA and
arterial pressure does indeed exist within the central nervous
system (CNS), but that it operates independently of the arterial
baroreceptor reflex.
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Invited Review
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THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
Table 1. Summary of indirect and direct assessment of
sympathetic nerve activity in sinoaortic denervated animals
Species
Indirect Assessment
of SNA
Direct Assessment
of SNA
Level of
SNA
Reference
Rat
Rat
Rat
Baboon
PNE
GB
—
PNE
—
—
RSNA
—
Normal
Normal
Normal
Elevated
(2, 11)
(3, 65)
(6, 41)
(73)
Indirect measures include measurement of plasma norepinephrine concentration (PNE) and the depressor response to acute ganglionic blockade (GB).
Direct measurements of renal sympathetic nerve activity (RSNA) are based on
between animal comparisons. SNA, sympathetic nerve activity; dashes indicate data not available.
AJP-Regul Integr Comp Physiol • VOL
sure is not valid. This conclusion then leads to the question:
what is controlling the long-term level of RSNA and arterial
pressure?
Alterations in the afferent limb of the reflex: Chronic unloading of arterial baroreceptors. The use of SAD animals to
study the long-term role of arterial baroreceptors in the regulation of SNA and arterial pressure is complicated by the fact
that chronic denervation may result in subsequent changes
within the terminal synaptic fields of these primary afferents,
leading to subsequent alterations in synaptic contacts within
the reflex pathway (neural plasticity). Therefore, it may be
incorrect to assume that SAD mimics a physiological reduction
in arterial baroreceptor activity with no other changes in the
reflex pathway. In other words, the SAD animal may be
“rewired” and therefore not be comparable to an intact animal
with a chronic decrease in baroreceptor nerve activity.
To circumvent this issue, Thrasher developed a novel surgical method for chronic unloading of arterial baroreceptors in
the dog in which baroreceptors from one carotid sinus and the
aortic arch are denervated and the perfusion pressure of the
remaining innervated carotid sinus is decreased by ligation of
the common carotid artery (78). This resulted in neurogenic
hypertension that was sustained for 7 days and rapidly reversed
when the carotid sinus pressure was returned to normal by
removal of the ligation. These results suggested that decreasing
arterial baroreceptor input to the brain did indeed result in
sustained neurogenic hypertension, and perhaps this model was
a more physiological approach to study the long-term influence
of baroreceptors on regulation arterial pressure than the SAD
model.
However, as discussed above, the time course of the normalization of arterial pressure after SAD in the dog is 2–3 wk,
and therefore it is important to follow the time course of
arterial pressure longer than 1 wk after unloading. Thrasher has
recently conducted such studies in which arterial pressure was
measured in conscious dogs for 35 days following either SAD
or baroreceptor unloading (77). Similar to the previous study
(78), arterial pressure was increased ⬃ 25 mmHg 7 days after
unloading. However, pressure subsequently returned toward
control such that by the 4th wk after unloading, pressure was
only slightly above normal levels. By comparison, arterial
pressure was increased to a similar degree 1 wk after SAD but
returned to control levels more rapidly than that observed after
unloading and was normal within 3 wk after SAD.
Inspired by the initial report by Thrasher (78), we recently
applied a similar strategy, with some modifications, to study
baroreceptor unloading in the conscious rabbit. Rabbits were
instrumented with telemetry transmitters for the measurement
of arterial pressure and underwent aortic baroreceptor denervation and allowed to recover. Subsequently, carotid baroreceptors were chronically unloaded bilaterally by placing
0.35-mm silver clips on both common carotid arteries. Although preliminary at this stage, our results are consistent in
that after carotid artery clipping, arterial pressure increased at
the same rate and magnitude to that seen after SAD in the
rabbit. More importantly, arterial pressure returned to control
levels within 1–2 days after bilateral carotid artery stenosis (FD
McBryde, JW Osborn and SC Malpas, unpublished observations).
Taken together, the results of the baroreceptor unloading
studies in the dog and rabbit, along with the studies in SAD
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On the basis of measurements of arterial pressure, heart rate,
and daily sodium excretion, we concluded that the return of
arterial pressure 2–3 days after SAD in the rat was not due to
pressure natriuresis/diuresis. This was based on the observation
that cumulative sodium balance was actually positive, rather
than negative, over the first 4 days following SAD. This
occurred despite elevated renal perfusion pressure, and we
concluded this was due to increased RSNA during this period.
However, by the fifth day after SAD arterial pressure, sodium
balance and heart rate had all returned to normal. On the basis
of these results, we hypothesized that the normalization of
arterial pressure following SAD was due to the return of
cardiac, renal, and vasomotor SNA after SAD (64). It is
important to note that a similar pattern was observed after
denervation of aortic baroreceptors alone, suggesting that partial or complete arterial baroreceptor denervation results in the
same steady-state responses of arterial pressure and sympathetic activity (64). Although this conclusion was based on
functional responses to SNA, it is supported by indirect measures of SNA such as plasma norepinephrine (2, 11) and the
depressor response to ganglion blockade (3, 65) in SAD rats
(See Table 1). More recently, direct recordings of RSNA in
conscious rats, albeit only hours after electrode implantation,
also suggest that RNSA returns to control levels after SAD (6,
41). Although each of these indices of SNA have their limitations, in combination, they provide compelling evidence that
the long-term basal level of RSNA is regulated independent of
arterial baroreceptor input. This conclusion remains to be
confirmed by direct continuous recordings of SNA in animals
fully recovered from surgical preparation in their home cage
environment. It is important to acknowledge that in one report
neither arterial pressure nor plasma norepinephrine were normalized 3 wk after SAD in baboons (73). However, as discussed above this may be the result of a slower time course of
normalization of both SNA and arterial pressure following
SAD in the nonhuman primate.
These studies suggest that arterial pressure eventually returns to normal after SAD as a result of SNA returning to
baseline levels rather than secondary to pressure natriuresis/
diuresis. It is important to note that the normalization of SNA
after SAD cannot be explained by compensation of intact
cardiopulmonary reflexes, as recently reviewed by Sved and
colleagues (76). Taken together, these findings suggest that the
long-term levels of SNA are regulated independent of the
arterial baroreceptor reflex and that extrapolation of the acute
RSNA-baroreflex curves to long-term control of arterial pres-
Invited Review
THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
IMPAIRMENT OF ARTERIAL BAROREFLEX CONTROL
OF RSNA AS A PRIMARY CAUSE OF
SALT-DEPENDENT HYPERTENSION
The focus of the discussion above was on the contribution of
baroreflex control of RSNA in determining the basal level of
arterial pressure in normal animals in the absence of environmental stress or known hypertensive stimuli. Overall, the
literature indicates that arterial baroreceptors have little to no
influence on the long-term basal level of arterial pressure or
RSNA under nonstressed conditions. In regard to whether the
arterial baroreceptor reflex chronically buffers stimuli known
AJP-Regul Integr Comp Physiol • VOL
to elevate arterial pressure, Cowley et al. have rejected this
notion on the basis of the effect of SAD on the development of
several models of experimental renovascular hypertension in
the dog (21). However, other studies suggest that the long-term
salt-sensitivity of arterial pressure is dependent on normal
baroreceptor reflex function.
The RSNA-baroreceptor reflex in genetic models of saltsensitive hypertension. The idea that a primary impairment of
the baroreceptor reflex arc shown in Fig. 1 contributes to the
development of hypertension in the Dahl salt-sensitive (DS) rat
is supported by numerous studies demonstrating resetting both
peripherally (4) and centrally (28, 29). However, it is virtually
impossible to determine whether baroreflex impairment is the
primary cause of salt-sensitive hypertension in this model since
these rats also exhibit impaired vascular (8) and renal (70, 71)
function at an early age. It has been reported that RDNX
attenuates salt-sensitive hypertension in this model, suggesting
that an increase in RSNA may be involved (62). But this may
not necessarily be due to altered baroreceptor reflex per se, as
there is evidence that salt-induced changes in sympathetic
activity are driven by forebrain sites that project to the RVLM
(75). If this is true, then the salt-dependent hypertension may
not be the result of impairment of the baroreceptor reflex arc
shown in Fig. 1 but rather a salt-induced activation of forebrain
sympathoexcitatory sites.
Further evidence for a primary role of impaired baroreceptor
reflex control in the development of salt-sensitive hypertension
is provided from the studies of Weinstock and colleagues (80)
using normotensive rabbits bred for differences in cardiac
baroreflex sensitivity (79, 80). By selectively breeding rabbits
in which the gain of the cardiac baroreflex is decreased, they
have demonstrated that salt-dependent hypertension is correlated with reduced gain of the cardiac baroreflex. More importantly, this model of hypertension is prevented by renal denervation, suggesting that it is dependent on activation of RSNA.
However, as with the DS rat, this model could also be due to
a salt-induced activation of RSNA independent of the arterial
baroreceptor reflex. Without a detailed understanding of how
central sympathetic pathways are contributing to the decreased
gain of the cardiac baroreflex, this possibility remains open.
Salt-sensitive hypertension in SAD animals. A more direct
approach to determine whether a primary impairment of the
arterial baroreceptor reflex results in salt-sensitive hypertension is to measure the effect of increasing dietary salt intake on
arterial pressure in normal and SAD animals. Howe and
coworkers were the first to demonstrate, using tail-cuff measurements of arterial pressure, that SAD rats became hypertensive when consuming a high-salt diet (38). This observation
was later confirmed by direct measurements of arterial pressure
in SAD rats in both Howe’s laboratory (39) and ours (67).
We recently investigated salt-sensitive hypertension in SAD
rats in more detail using continuous telemetric measurements
of arterial pressure (66). As shown in Fig. 2A and discussed
above, the basal level of arterial pressure in intact (shamoperated) and SAD rats was similar when both groups were
consuming a normal salt (0.4% NaCl) diet. However, increasing dietary salt to 4.0% NaCl resulted in a sustained increase in
arterial pressure in SAD but not sham-operated rats during the
3-wk period of 4.0% NaCl intake. Note, however, that the
difference between groups was not apparent until ⬃10 days
after increasing salt intake. Similarly, increasing salt intake
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animals reviewed above, suggest that arterial pressure returns
to normal after SAD and unloading, although the time course
may be slightly different. These results suggest that long-term
control of arterial pressure occurs independently of arterial
baroreceptor input to cardiovascular sympathetic networks in
the brain. If this proves to be true, it again raises the question:
Is there a nonbaroreflex neural control system for long-term
control of SNA and arterial pressure?
Alterations in the efferent limb of the reflex: Effect of renal
denervation on basal levels of arterial pressure. If baroreceptor reflex control of RSNA is important in the long-term
control of arterial pressure, then renal denervation (RDNX)
should affect the basal level of pressure. Surprisingly, despite
the numerous studies in which RDNX animals have been
studied for a variety of experimental questions, it has been
generally thought that RDNX has no effect on arterial pressure
in normotensive salt-replete animals. However, in a recent
study we investigated the effect of RDNX on the long-term
salt-sensitivity of arterial pressure in conscious rats. Arterial
pressure was measured 24 h/day by radio telemetry in shamoperated and RDNX rats. Surprisingly, we found that RDNX
rats consistently had a lower arterial pressure than shamoperated rats (43). Although the magnitude of the decrease in
arterial pressure was modest, ⬃10 mmHg, it was statistically
significant and remained constant over a 100-fold range of
dietary salt intake, suggesting it was not related to alterations in
sodium and water balance. In addition, this effect was observed
immediately (less than 1 h) following RDNX, further suggesting that this hypotensive effect was not related to denervation
natriuresis and diuresis. In more recent studies, we have shown
that denervation of one kidney lowers pressure half as much as
bilateral denervation (44), and denervation of the sole remaining kidney in unilaterally nephrectomized rats decreases pressure to the same extent as bilateral denervation in rats with two
kidneys (45). The mechanisms responsible for hypotension in
renal denervation remain to be firmly established but likely
involve loss of neurogenic control of renin release (44), loss of
renal vasomotor activity, and/or impairment of renal afferent
control of sympathetic activity (51, 74).
This observation supports the idea that the CNS is indeed
important in the maintenance of arterial pressure in normal
animals, as RDNX lowers pressure in the presence of other
arterial pressure control systems, in particular the “renal-body
fluid” arterial pressure control system, which is proposed to
have “infinite gain” (34). However, since baroreceptor-independent pathways can control RNSA, this does not necessarily
indicate that the arterial baroreceptor reflex regulates the basal
level of RSNA.
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Invited Review
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THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
further (8.0% NaCl) resulted in a slightly greater increase in
arterial pressure for an additional 3 wk. Finally, switching both
groups back to a 0.4% NaCl diet resulted in an immediate
normalization of arterial pressure in SAD rats.
These results, based on the 24-h averages of arterial pressure, were originally seen as evidence that arterial baroreceptors are important in the long-term control of arterial pressure
during chronic increases in dietary salt. Indeed, this study has
been cited by others as evidence for a long-term role of arterial
baroreceptors in the regulation of arterial pressure (56, 78).
However, further examination of the data on an hour-by-hour
basis leads to a possible alternative explanation. Plotted in Fig.
2B are the hourly averages for the final 72 h of each level of
dietary salt for sham-operated and SAD rats. The vertical gray
bars indicate the night-cycle and the white bars represent the
day-cycle. Note that the normal circadian rhythm of arterial
pressure in sham-operated rats was unaffected by the level of
dietary salt. In contrast, SAD rats exhibited marked increases
AJP-Regul Integr Comp Physiol • VOL
in arterial pressure during the night, such that pressure increased ⬃20 mmHg over 12 h on the 4.0% salt diet and ⬃30
mmHg over 12 h on the 8.0% salt diet. It is also important to
note that as soon as the light cycle began, arterial pressure fell
steadily such that by mid-day, it was back to near-normal
levels. This observation is important for two reasons. First, it
demonstrates that single intermittent measurements of arterial
pressure each day could potentially give erroneous results
depending on the time of day that arterial pressure is measured.
Second, the nighttime increases in pressure are likely due to the
fact that rats ingest their food and water during the night
resulting in 12-h oscillatory osmotic and volume stimuli. Since
studies in the rat have shown it takes 48 h for arterial baroreceptors to reset (52), these 12-h volume and sodium loads
could easily be buffered in the baroreceptor reflex. This is
consistent with the more accepted role of the baroreceptor
reflex in the short-term regulation of arterial pressure rather
than long-term control.
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Fig. 2. Comparison of mean arterial pressure
(MAP) responses to increased dietary salt in
sinoaortic denervated (SAD) and sham-operated
rats. A: 24-h averages of MAP during consumption of normal (0.4% NaCl) and high (4.0% and
8.0% NaCl) salt diets. B: Hourly averages of
final 72 h of MAP on each level of dietary salt.
See text for details. [From Osborn and Hornfeldt
(66)].
Invited Review
THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
AJP-Regul Integr Comp Physiol • VOL
balances between groups when dietary salt intake was either
increased or decreased 10-fold from normal. Although it is
possible, since balance measurements were conducted over a
24-h period using standard metabolic cages, that small immeasurable changes in balance did occur in this study, it is clear
that such differences had absolutely no impact on the regulation of arterial pressure as determined by continuous telemetric
monitoring.
These findings can be interpreted in several ways. First, it is
possible that under the conditions of this study, dietary salt
loading has no effect on RSNA. Although changes in dietary
salt theoretically influence RSNA chronically, this has not been
established by direct nerve recordings in conscious animals
before and after changes in dietary salt intake. Second, the
contribution of renal nerves to the maintenance of sodium
balance has been demonstrated under conditions of extreme
changes in sodium intake (30), but they may play a minor role
in the regulation of sodium balance over a more physiological
range of dietary salt intake in the rat. Third, although there is
a proposed theoretical link between sodium and water balance
and arterial pressure (34), this link may not be as strong as
proposed and it may be incorrect to assume that changes in
sodium balance are always translated to changes in arterial
pressure. Finally, since RDNX results in essentially “zero”
functional RSNA, in contrast to what is likely to be a normal
level of RSNA in SAD animals (see discussion above), this
may lead to different responses of SAD and RDNX rats to salt
loading.
In summary, despite a well-known theoretical role for
baroreceptor reflex control of RSNA regulating the long-term
salt-sensitivity of arterial pressure under physiological conditions, the evidence supporting this hypothesis is not particularly convincing. Indeed, the physiological links between dietary salt and RSNA, changes in RSNA and sodium balance,
and finally, sodium balance and arterial pressure, have yet to be
fully defined.
A NEURAL SET POINT FOR THE LONG-TERM CONTROL OF
ARTERIAL PRESSURE: BEYOND THE ARTERIAL
BARORECEPTOR REFLEX
This review addressed the hypothesis that arterial baroreceptor reflex control of the kidney is important in the long-term
control of arterial pressure. However, several observations are
inconsistent with this hypothesis. First and foremost, a large
number of studies conducted over the past two decades, utilizing indirect and direct measures of RSNA, lead to the conclusion that RSNA and arterial pressure return to normal levels
after surgical denervation of arterial baroreceptors. Although
similar measurements of RSNA have not been carried out in
the newer model of baroreceptor unloading, early indications
are consistent with the view that arterial pressure also returns
toward normal in this model. Second, although the long-term
salt sensitivity of arterial pressure is increased in SAD animals,
continuous monitoring of arterial pressure indicate this is due
to impairment of the short-term buffering of acute salt and
water loads. Finally, although renal denervation chronically
lowers arterial pressure it does not alter the long-term salt
sensitivity of arterial pressure. Taken together, these studies
utilizing different experimental approaches in different species,
are consistent with the “classic” view that the arterial barore288 • APRIL 2005 •
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The route and nature of salt and water loading is a subtle, but
important distinction to make when comparing studies on the
role of arterial baroreceptors in salt-dependent hypertension.
For example, in the experiments by Cowley et al. (21) studying
the effects of increases in salt intake in models of renovascular
hypertension in the dog, salt intake was controlled by intravenous infusion and was increased in a “square wave” fashion by
simply increasing the intravenous dose of saline (21). Under
these “static” conditions, it is likely that the arterial baroreceptor reflex does indeed adapt, in contrast to the 12-h oscillatory
salt and water load in the study above. Moreover, intravenous
salt loading is unphysiological in that it bypasses the hepatoportal osmoreceptors, which have been shown to influence
central autonomic pathways (1, 12, 13, 50), RSNA (42, 59, 60),
and renal function (37, 60).
The above discussion raises an important question: what
defines short-term vs. long-term control of arterial pressure? If
baroreceptor dysfunction results in salt induced increases in
arterial pressure over a period of hours, is this a disruption of
short-term or long-term arterial pressure control system? Relative to studies on baroreceptor control of sympathetic nerve
activity, it may be argued that this is indeed dysfunction of a
long-term arterial pressure control system. However, from the
perspective of the pathogenesis of hypertension, which occurs
over a much longer timescale, this would appear to be disruption of a short-term control system. Although the authors take
the latter perspective, the issue of what constitutes short-term
and long-term control of arterial pressure remains to be defined.
Baroreflex control of RSNA during chronic increases in
dietary salt. If the baroreceptor reflex controls RSNA during
changes in dietary salt intake, then the increased salt-sensitivity
of arterial pressure in SAD animals may be due to impaired
baroreflex control of the kidney. There is indirect evidence that
RSNA is chronically suppressed in dogs on a high-salt intake
(54), but unfortunately, this has yet to be confirmed by continuous direct recordings of RSNA before and after chronic salt
loading. We did not observe an impaired ability of SAD rats to
excrete a dietary salt load, suggesting that impairment of the
baroreceptor reflex control of the kidney is not the cause of
salt-dependent hypertension in SAD rats (67). This is contradicted by a recent report demonstrating that SAD rats had an
impaired ability to excrete a salt load (23). Comparison of
these studies is not straightforward since, in that latter report
(23), salt and water were administered as a saline drinking
solution, rather than the more physiological route of in the diet,
and arterial pressure was not measured in the conscious state.
If neural control of the kidney is important in the long-term
regulation of arterial pressure during changes in dietary salt
intake, then RDNX should increase the long-term salt sensitivity of arterial pressure. Consistent with this hypothesis,
unilateral RDNX impairs urinary sodium excretion from the
denervated kidney, compared with the innervated kidney, of
the dog (54). On the basis of these findings and the theoretical
relationship between sodium balance and arterial pressure (34),
we predicted that bilateral RDNX should increase the longterm salt-sensitivity of arterial pressure. However, we found no
differences between RDNX and sham-operated rats in the
salt-sensitivity of arterial pressure over a 100-fold range
(0.04% to 4.0% NaCl diet) of dietary salt intake (43). We also
did not observe any differences in daily sodium or water
R851
Invited Review
R852
THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
Fig. 3. Schematic illustration of hypothetical CNS-MAP set point system for
long-term control of arterial pressure. See text for details.
AJP-Regul Integr Comp Physiol • VOL
same pathways are responsive to changes in the osmolality of
body fluids (47, 58). A shown in Fig. 3, the arterial baroreceptor reflex controls the short-term variability of arterial pressure
in the classic sense as reviewed above. However, the basal
level of both SNA and arterial pressure, over long periods of
time, are controlled by this nonbaroreflex system in which the
set point is established by the integration of multiple inputs
linked to arterial pressure. Because both of these systems
converge on sympathetic premotor neurons in the RVLM,
changes in activity of the CNS-MAP set point system will
clearly alter the characteristics of the arterial baroreceptor
reflex (central resetting). However, the converse is not true in
that changes in the arterial baroreceptor reflex will not alter the
operation of the CNS-MAP set point control system. This
explains why SAD does not alter the basal level of SNA.
Evidence that such a CNS-MAP set point exists and is
altered in hypertension is suggested by studies of angiotensininduced hypertension. There is now abundant evidence that
circulating ANG II chronically increases SNA via an action on
central sympathetic neural pathways (26). Although the details
have not been entirely elucidated, these long-term sympathoexcitatory actions of ANG II are generally thought to occur as
a result of binding to AT1 receptors in circumventricular
organs such as the area postrema of the hindbrain and the
subfornical organ of the hypothamalus. Lesions from both of
these sites prevent the hypertensive response to exogenous
ANG II (27, 36) and the chronic hypotensive response to AT1
receptor blockade with losartan (14, 15). The sympathoexcitatory actions of ANG II are independent of the baroreceptor
reflex since the steady-state level of angiotensin-induced hypertension is not affected by sinoaortic denervation (18). These
observations support the hypothesis, originally proposed in the
1970s (10, 25), that ANG II causes hypertension via actions on
the central neural pathways, which ultimately act on the
RVLM to increase sympathetic activity (26).
But what is the evidence that ANG II acts on a CNS-MAP
set point to cause hypertension? Neurogenic hypertension
caused by hormones that regulate sodium and water homeostasis, such as ANG II, could simply result from pathological activation of the sympathetic nervous system. At the
present time, there is not enough data to accept or reject the
CNS-MAP set point hypothesis, but it does provide a logical
explanation for long-term regulation of SNA and arterial
pressure. It is important to note that this concept has been
suggested in the past. More than 20 years ago, Bohr hypothesized that DOCA-salt hypertension is due mineralocorticoid actions on hypothalamic circumventricular organs and
“resetting of a pressure-regulating center in the hypothalamus” (9). However, this hypothesis has yet to be firmly
established within the hypertension field and remains to be
challenged.
Testing the CNS-MAP set point hypothesis will be difficult since it is likely to be an extremely complex system
involving the integration of multiple inputs, including hormone plasma concentrations (circumventricular organs),
body fluid osmolality (central and peripheral osmoreceptors), and cardiovascular pressures (arterial and cardiopulmonary baroreceptors). Additional inputs related to energy
metabolism, immune system activity, stress etc. are also
likely to influence the CNS-MAP set point. Similarly, it is
likely that this system controls arterial pressure by regula288 • APRIL 2005 •
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ceptor reflex is important in the short-term control of SNA and
arterial pressure but has little importance in long-term regulation of these variables.
The failure of SAD to alter long-term levels of arterial
pressure was originally used as an argument against a role for
the entire nervous system in arterial pressure regulation (32).
This is understandable because these interpretations were made
at a time when the arterial baroreceptor reflex was seen as the
primary neural control system for arterial pressure. Since that
time, our understanding of autonomic control of the circulation, in particular, forebrain sites that influence SNA, have
grown tremendously, and we now need to incorporate this new
knowledge into an updated neural model for long-term control
of arterial pressure.
If we accept that RSNA is normal in the absence of arterial
baroreceptor input, we are then led to question of whether a
baroreceptor-independent, central nervous system set point
exists for the long-term control of SNA and mean arterial
pressure (CNS-MAP set point). The term “set point” is used to
designate a true control system for SNA and arterial pressure
rather than a system that simply modulates SNA and arterial
pressure without regard to the maintenance of a long-term level
of these variables. There are several neural pathways within the
central nervous system that modulate the basal level of SNA
chronically, but are these pathways part of a control system
that has a true set point for arterial pressure? If so, what type
of “error signals” (inputs) cause primary shifts in this set point?
Finally, what efferent pathways (outputs) mediate the longterm changes in arterial pressure? These are questions that
must be addressed by future research.
A simplified conceptual scheme of this system is illustrated
in Fig. 3. The neuroanatomical details of this theoretical system
remain to be fully elucidated, but it is logical to suggest that it
incorporates pathways involved in the maintenance of body
fluid homeostasis (46, 58). These pathways are responsive to a
number of signals linked to arterial pressure and regulate key
autonomic nuclei which ultimately influence the activity of
sympathetic premotor neurons in the RVLM. In addition,
hormones linked to sodium and water homeostasis such as
ANG II, vasopressin, and aldosterone modulate sympathetic
activity via binding in circumventricular organs and subsequent modulation of autonomic activity (47). Finally, these
Invited Review
THE NERVOUS SYSTEM AND LONG-TERM CONTROL OF ARTERIAL PRESSURE
Perspectives
Despite recent evidence suggesting the arterial baroreceptor
reflex plays an important role in the long-term control of SNA
and arterial pressure, a critical evaluation of the literature to
date is most consistent with a short-term role of this reflex in
cardiovascular regulation. A more important and complicated
picture is emerging in which the long-term level of SNA is
regulated in the absence of arterial baroreceptor input to the
brain. Indeed, numerous studies suggest the existence of a
long-term central nervous system control system that operates
independently of the arterial baroreceptor reflex. Despite the
complexity of this theoretical system, our future success in
understanding the pathogenesis of neurogenic hypertension
could be aided by studies designed to test the CNS-MAP set
point hypothesis.
ACKNOWLEDGMENTS
We would like to acknowledge the constructive comments of Simon
Malpas, Carolyn Barrett and Rohit Ramchandra during the preparation of this
manuscript.
GRANTS
Work from the author’s laboratory was supported by a grant from the
National Heart, Lung, and Blood Institute of the National Institutes of Health
(HL64178). Part of this work was conducted while J. W. Osborn was on
sabbatical leave in the laboratory of Simon Malpas at the University of
Auckland.
AJP-Regul Integr Comp Physiol • VOL
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