Cardiovascular Research 61 (2004) 238 – 246
www.elsevier.com/locate/cardiores
Review
Interactions between the sympathetic nervous system and the
kidneys in arterial hypertension
Olaf Grisk *, Rainer Rettig
Department of Physiology, Ernst-Moritz-Arndt-University of Greifswald, Greifswalder Str. 11c, D-17495 Karlsburg, Germany
Received 1 September 2003; received in revised form 31 October 2003; accepted 18 November 2003
Time for primary review 28 days
Abstract
Elevated sympathetic activity changes renal function and accelerates the development of hypertension. Principles of sympatho-renal
interactions in chronic hypertension are reviewed. Alterations in the ontogeny of the sympathetic nervous system and the kidney, inherited
abnormalities in sensory receptor function and exaggerated responsiveness to mental stress contribute to inappropriately high sympathetic
activity in primary or essential hypertension. Careful characterization of clinical study populations shows that elevated sympathetic activity
and ‘‘essential’’ hypertension are not unequivocally associated. Prospective clinical studies which investigate a broader array of physiological
functions and experiments in recombinant inbred rodents with less traumatic nerve recording techniques than currently available will help to
define under which conditions elevated sympathetic activity is indeed a cause of primary hypertension. Signals arising from the kidney which
activate the renin – angiotensin system and afferent renal nerves increase sympathetic activity. These mechanisms importantly contribute to
the pathogenesis of hypertension secondary to renal artery stenosis and end-stage renal disease.
D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Arterial hypertension; Kidney; Sympathetic nervous system
1. Introduction
The sympathetic nervous system contributes importantly
to arterial pressure control under varying conditions by
modifying cardiac output, peripheral vascular resistance
and renal function. The system can exert powerful acute
pressor actions and participates in the pathophysiology of
chronic arterial hypertension. The renal volume/pressure
control system is regarded to dominate physiological longterm arterial pressure regulation because of its infinite
capability to return altered arterial pressure to its original
level by increasing or decreasing water and electrolyte
excretion in response to elevated or reduced systemic
arterial pressure [1]. Activation of sympathetic nerves to
the kidney increases tubular sodium reabsorption, renin
release and renal vascular resistance [2]. These actions
contribute to long-term arterial pressure elevations by shift-
* Corresponding author. Tel.: +49-3834-8619300; fax: +49-38348619310.
E-mail address: [email protected] (O. Grisk).
ing the pressure-natriuresis curve to the right [2]. Signals
generated in renal sensory receptors and conducted via renal
afferent nerves modify efferent sympathetic nerve activity
with consequences for arterial pressure regulation [2]. The
aim of the present paper is to review recent work that
demonstrates how the kidneys and the sympathetic nervous
system interact in the pathophysiology of experimental and
human arterial hypertension.
2. Quantification of renal sympathetic nerve activity
Any in-depth consideration of the interaction between the
sympathetic nervous system and the kidney in arterial hypertension relies on reliable methods to quantify renal sympathetic nerve activity (RSNA). In experimental animals RSNA
can be assessed by multifiber or single unit recordings of
electrical activity. With multifiber recordings RSNA cannot
be compared reliably in terms of absolute voltages. To
compensate for this problem several investigators have used
sophisticated methods of nerve traffic analysis. An important
methodological progress has recently been made by the
0008-6363/$ - see front matter D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2003.11.024
O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
introduction of telemetric renal nerve recordings in rabbits
[3]. Once this technology becomes available for smaller
rodents it will allow for long-term recordings of RSNA in
more widely used animal models of arterial hypertension.
For obvious reasons RSNA cannot be directly assessed in
humans and measurements of SNA in peroneal nerves are
only indirect evidence for what may happen in renal
sympathetic nerves. To obtain an estimate of renal sympathetic nerve activity in humans, radiotracer techniques have
been applied to measure norepinephrine spillover in renal
venous plasma [4,5].
3. Primary or essential hypertension
There is ample evidence for elevated sympathetic nerve
activity in experimental and human primary (essential)
hypertension. The sympathetic nervous system may act
through the kidney to cause or maintain arterial hypertension. The hypertensinogenic effects of the sympathetic
nervous system on the kidney may start as early as ontogeny.
3.1. Development of renal sympathetic innervation
The development of the kidney has been extensively
studied in normotensive and hypertensive rats [6– 14]. In
this species afferent renal innervation has fully developed
around birth while efferent sympathetic renal innervation
continues to develop from embryonic day 16 through postnatal day 21 [6]. During postnatal weeks 2 – 4, a steep rise in
renal norepinephrine concentration and turnover occurs [7].
Afferent and efferent renal innervation depend on the actions
of neurotrophins such as nerve growth factor (NGF), neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic
factor (GDNF) [8]. Besides its role in the development of
renal innervation GDNF is also required for normal renal
morphogenesis in rats and mice [9]. The actions of GDNF on
the developing kidney may have a major impact on longterm arterial pressure. Thus, mice carrying only one copy of
the GDNF gene have fewer and larger glomeruli associated
with an increase in arterial pressure by about 20 mm Hg
compared to wild type controls [15].
Interestingly, whole kidney glomerular filtration rate
(GFR) and renal blood flow are normal in GDNF +/- mice
[15] and the mechanisms by which a diminished GDNF
action during ontogeny causes long-term blood pressure to
rise are currently not well understood. Circumstantial evidence suggests that these mechanisms may be related to the
trophic actions of GDNF. Thus, in normotensive Sprague –
Dawley rats the maturation of noradrenergic projections to
various organs including the kidney coincides with a decline
in local DNA synthesis [7] indicating that the sympathetic
nervous system may have negative trophic effects during
renal development. In keeping with this finding, neonatal
sympathectomy elicits elevations in renal RNA and protein
concentrations during renal maturation, i.e., during postnatal
239
days 10– 20 [14]. In spontaneously hypertensive rats (SHR)
renal sympathetic innervation is enhanced [10,16,17] and
neonatal sympathectomy is associated with a decrease in
long-term arterial pressure. Together, these findings suggest
that a certain level of trophic stimulation during renal
development may be required in order to maintain arterial
pressure at a normal level whereas a lack of trophic
stimulation such as in GDNF +/ mice or in rats with
increased renal sympathetic innervation may contribute to
the pathogenesis of arterial hypertension.
On the other hand, renal sympathetic hyperinnervation
alone is probably not sufficient to cause arterial hypertension. Thus, in SHR renal sympathetic innervation is more
dense [16] and develops faster [10] during the first two
postnatal weeks than in normotensive Wistar – Kyoto rats
(WKY). Furthermore, renal norepinephrine content is approximately two times higher in newborn [10] and approximately 1.5 – 3 times higher in adult SHR [17] compared to
age- and sex-matched WKY. Since renal NGF mRNA
expression was elevated in newborn SHR compared to
WKY [11] or normotensive Donryu rats (DRY) [12] it has
been suggested that this factor may contribute to renal
sympathetic hyperinnervation in SHR [13]. In order to
investigate the effects of NGF on renal sympathetic innervation and long-term arterial pressure, normotensive Wistar
rats were treated with the substance from birth to postnatal
week 8. This treatment resulted in noradrenergic hyperinnervation of several organs including the kidney [18].
However, long-term arterial pressure was not elevated [18].
To further investigate the role of early renal sympathetic
innervation for the development of primary hypertension,
we transplanted kidneys from neonatally sympathectomized
SHR into untreated SHR recipients [19] (Fig. 1). SHR
Fig. 1. Time course of telemetrically recorded mean arterial pressure (MAP)
in SHR transplanted with a kidney from hydralazine-treated donors (circles,
n = 10) and in SHR transplanted with a kidney from neonatally sympathectomized donors (triangles, n = 10). Asterisks indicate significant differences
between groups ( p < 0.05). Recipients of a kidney from neonatally
sympathectomized donors showed less sodium sensitivity and lower final
arterial pressure levels. Reprinted with permission from Ref. [19].
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O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
recipients of a kidney from hydralazine-treated donors
served as controls. Transplantation of a kidney from sympathectomized donors was associated with a decrease in
long-term arterial pressure of about 20 mm Hg and a
reduction in sodium sensitivity of arterial pressure. These
findings suggest that neonatal sympathetic innervation in
SHR causes changes in renal function that are involved in
the development and maintenance of hypertension. The
nature of these alterations is currently unclear. Initial studies
did not show major effects of neonatal sympathectomy on
renal morphology [19]. A detailed investigation of neonatal
sympathectomy-induced changes in SHR renal function is
currently in progress.
There is evidence from clinical studies [5] that sympathetic innervation of cardiovascular organs including the
kidney is enhanced in patients with essential hypertension.
The specific contribution of the enhanced sympathetic
innervation to the pathogenesis of essential hypertension
remains to be determined.
3.2. Renal sympathetic nerve activity in primary (essential)
hypertension
In several experimental forms of primary and obesityrelated hypertension there is widespread increased sympathetic nerve activity. Recent evidence for increased sympathetic nerve activity in SHR versus WKY includes (1)
elevated norepinephrine concentrations and tyrosine hydroxylase activities in skeletal muscle and white adipose
tissue [20], (2) increased excitability of superior cervical
ganglion cells [21], and (3) increased plasma norepinephrine levels [20], although the latter have not always been
confirmed [22].
There is also evidence for increased sympathetic nerve
activity in obese compared to lean Zucker rats. Thus,
ganglionic blockade decreased blood pressure more in obese
than in lean Zucker rats, indicating a stronger dependence of
blood pressure on sympathetic activity in obese than in lean
rats [23]. Furthermore, sympathetic nerve activity to brown
adipose tissue was higher in obese than in lean Zucker rats,
although this difference was not statistically significant [24].
Studies in essential hypertensive humans also indicate
that there is widespread increased sympathetic nerve activity. Thus, cardiac norepinephrine spillover [25] and muscle
sympathetic nerve activity (MSNA) [26 – 28] were elevated
in essential hypertensive patients compared to normotensive
controls.
Many of the above mentioned indices of increased
sympathetic nerve activity in hypertension do not necessarily
mean that the activation includes renal sympathetic fibres.
Thus, peripheral sympathetic nerve activity in response to
reflex activation or centrally generated sympathetic tone may
be subject to organ specific differential regulation. The
following two examples from recent experimental and clinical work in normotensive subjects may serve to illustrate
this point. Firstly, in Sprague – Dawley rats the gain of
arterial baroreflex-induced changes in sympathetic nerve
activity was higher in renal than in adrenal or lumbar
sympathetic fibres [29]. Secondly, in healthy humans acute
intravenous administration of the angiotensin I-converting
enzyme (ACE) inhibitor, enalaprilat, caused a 50% rise in
renal norepinephrine spillover while cardiac and total body
norepinephrine spillover remained unchanged indicating
selective activation of RSNA probably due to low-pressure
baroreceptor unloading [30].
Several recent studies [4,31 – 34] show that the increased
sympathetic nerve activity found in experimental and clinical primary (essential) and obesity-related hypertension
almost invariably includes renal sympathetic nerves. Thus,
RSNA was higher in SHR than in normotensive inbred rats,
and elevated RSNA cosegregated with an increase in arterial
pressure. A recent study [31] comparing SHR and WKY
suggests that increased oxygen radical formation may contribute to the chronically elevated RSNA in SHR. Thus,
intravenous administration of the superoxide dismutase
mimetic, tempol, (30 mg/kg) reduced arterial pressure by
40 mmHg in SHR and by only 20 mm Hg in WKY. The
decrease in blood pressure was accompanied by a reduction
in RSNA of 60% in SHR and only 30% in WKY [31].
Elevated RSNA was also found in conscious obese versus
lean Zucker rats [32] and in Wistar fatty versus Wistar lean
rats [33]. Finally, in patients with essential and obesityrelated hypertension renal norepinephrine spillover was
elevated by approximately 50% compared to lean normotensive controls [4,34].
In order to further investigate the role of renal sympathetic nerve activity for the development of primary hypertension researchers sought to specifically stimulate or block
this pathway. Increased RSNA can be mimicked by infusion
of norepinephrine into the renal artery with minimal spillover into the systemic circulation. In rats [35] and dogs
[36,37] this manoeuvre causes arterial hypertension. The
mechanisms mediating this form of experimental hypertension are controversial. Volume expansion was excluded in
two studies [35,36], but may have occurred in the third [37].
Interestingly, in the latter study [37] the decreased renal
sodium excretion in norepinephrine-infused dogs was not
necessarily associated with an increase in blood pressure,
shedding further doubt on the role of volume expansion in
this model of hypertension.
The renal artery norepinephrine infusion approach has
several limitations. It does neither mimic the temporal and
spatial pattern of norepinephrine release from renal sympathetic nerves nor does it account for the role of co-transmitters such as neuropeptide Y or ATP. Furthermore,
spillover of norepinephrine into the systemic circulation is
hard to avoid and may account for the failure to detect
significant volume expansion in this model [1].
An alternative approach to study the role of renal
sympathetic nerves for the pathogenesis of experimental
hypertension is by performing renal denervation in young
genetically hypertensive animals. Selective renal denerva-
O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
tion in juvenile genetically hypertensive animals delays, but
does not completely prevent the development of hypertension [2]. Even complete neonatal sympathectomy does not
reduce arterial pressure to entirely normotensive levels [19].
On first glance, these data suggest that increased renal
sympathetic nerve activity plays a major role in the pathogenesis of experimental primary hypertension. However,
they should be interpreted with caution. Thus, long-term
arterial pressure reductions in SHR can also be achieved by
measures that do not directly interfere with RSNA. For
example, transient treatment of prehypertensive SHR with
an ACE inhibitor [38], an AT1 receptor blocker, or hydralazine [39] (own unpublished observations) elicited chronic
reductions in arterial pressure that lasted well beyond the
cessation of treatment.
Furthermore, in experimental renal cross-transplantation
studies [40,41] recipients of a solitary SHR kidney invariably developed post-transplantation hypertension although the transplanted kidney was obviously denervated
and there was essentially no sympathetic reinnervation
during the experiment [42]. The development of hypertension in recipients of an SHR kidney graft was not
accompanied by sympathetic activation [43]. To further
investigate the potential role of the recipients’ sympathetic
nervous system for renal post-transplantation hypertension
we transplanted kidneys from untreated young SHR into
neonatally sympathectomized F1 hybrids derived from
crossing SHR and WKY [19]. SHR kidney grafts increased arterial pressure by about 20 mm Hg in sympathectomized and by about 35 mm Hg in sham-treated
recipients [19]. These data indicate that a generalized
reduction of sympathetic tone resets the renal volume/
pressure control system to reduced arterial pressure levels
241
and blunts the arterial pressure rise induced by an SHR
kidney graft (Fig. 2).
The modulatory role of the sympathetic nervous system in human hypertension is evident from the well
known antihypertensive effects of various types of treatment which block sympathetic activity either centrally or
peripherally. On the other hand, hypertension in humans
may develop under conditions where sympathetic tone is
greatly reduced. Thus, in a study population of 117
patients with autonomic failure more than 50% had
supine hypertension [44]. A recent study [45] showed
that in adult humans with low birth weight—a group with
a high prevalence of arterial hypertension—resting MSNA
was lower than in subjects with normal birth weight. To
our knowledge there is currently no data on renal norepinephrine spillover in this particular group of humans.
In young borderline hypertensive subjects neither MSNA
[46] nor resting plasma catecholamine concentrations were
elevated compared to normotensive controls [46,47]. Conversely, normotensive obese subjects showed a similar
rise in renal norepinephrine spillover as observed in both
lean hypertensive and obese hypertensive patients [34].
Several studies in humans showed that increased bodyweight with and without hypertension was associated with
elevated MSNA and plasma norepinephrine concentrations
[26,28,34,46].
These findings indicate that elevated sympathetic and in
particular elevated renal sympathetic activity is not a specific sign of (essential) hypertension. Possibly, a subgroup
of obese patients may be able to compensate for elevated
RSNA and does not develop high blood pressure. On the
other hand, elevated RSNA may be an epiphenomenon of
both obesity and hypertension which when present can
worsen hypertensive disease. Prospective studies and careful stratification of patients according to anamnestic and
clinical data [34,45] will help to further determine the causal
role of elevated (renal) sympathetic activity in the pathogenesis of human essential hypertension.
3.3. Arterial baroreceptors and renal sympathetic nerve
activity
Fig. 2. Mean arterial pressure (MAP) in sympathectomized (SHRxWKY)F1 hybrids (F1H) (closed symbols, n = 10) and sham treated F1H (open
symbols, n = 8) prior to transplantation with an SHR kidney and 6 weeks
after renal transplantation. Asterisks indicate significant differences
between groups ( p < 0.001). z indicates a significant interaction between
the factors treatment (sympathectomy, sham-treatment) and time after
transplantation of an SHR kidney ( p < 0.05). There was an exaggerated
arterial pressure rise in recipients with intact sympathetic nervous system
compared to sympathectomized recipients. Reprinted with permission from
Ref. [19].
There is evidence that compromised arterial baroreceptor
reflex function may lead to salt-sensitive hypertension [48 –
51], possibly via increased RSNA. Thus, the generalized
destruction of primary sensory afferents by neonatal capsaicin treatment facilitated the development of salt-induced
hypertension in rats [50,51]. In a more specific approach
chronic sinoaortic baroreceptor denervation caused normotensive rats to respond to a high-salt diet with increased
renal sodium retention associated with an increase in arterial
pressure [48,49]. Furthermore, chronic sinoaortic denervation increased the fluctuations in frequency and amplitude
of synchronised renal sympathetic discharges [52] (Fig. 3).
The discharge patterns of renal sympathetic nerves determine the degree of renal vasoconstriction and antinatriuresis
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O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
were kept on a high-salt diet [55]. Hypertension did, however,
cosegregate with a decreased responsiveness of renal afferent
nerve activity to elevations in renal pelvic pressure [56]
suggesting that a sensory system different from classical
arterial and cardiopulmonary baroreceptors may be related
to salt-sensitive hypertension.
Some degree of sensory dysfunction has also been found
in human essential hypertension, although its exact role in the
pathogenesis of hypertension has not been precisely defined.
Thus, the range of arterial baroreflex-induced changes in
heart rate was blunted by approximately 40% in essential
hypertensive patients compared to normotensive controls
[27]. On the other hand, arterial baroreflex-induced changes
in MSNA were unaltered except for being reset to higher
arterial pressure levels [27]. Since the sensitivity of baroreflex-induced changes in heart rate is to a large extend
genetically determined [57] inherited variations in arterial
baroreflex sensitivity may contribute to the genetically determined risk to develop hypertension.
Sensory dysfunction in human hypertension may not be
strictly confined to the cardiovascular system. Thus, young
subjects at risk for hypertension had decreased pain perception giving rise to the hypothesis that there may be a
common physiological mechanism for sensory dysfunction
and increased blood pressure [58].
3.4. Responsiveness to mental stress
Fig. 3. Histograms show relative frequencies of synchronized renal
sympathetic nerve discharges with regard to their amplitude (A) and time
interval (B). Data were obtained from 15 min recordings in conscious freely
moving rats (n = 9 per group) which underwent sham surgery (dotted lines)
or sinoaortic denervation (solid lines) three weeks before the recordings.
Sinoaortic denervated rats showed slightly greater fluctuations in the
amplitude of synchronized renal sympathetic nerve activity compared to
controls. Mode of time intervals between discharges and variability of the
time intervals between synchronized discharges were substantially elevated
in sinoaortic denervated rats (data from Ref. [52]).
[53]. These findings suggest that an impaired arterial baroreceptor reflex function may facilitate the development of
salt-sensitive hypertension via its effects on RSNA.
In keeping with this hypothesis many studies demonstrated an altered arterial and cardiopulmonary baroreceptor
reflex regulation of RSNA in inbred genetically hypertensive
versus normotensive rats (for review, see Ref. [2]). Recent
evidence from cosegregation studies [54 – 56] suggests, however, that the impaired cardiopulmonary reflex regulation of
RSNA seen in genetically hypertensive animals may not be
causally linked to hypertension. Thus, neither the degree of
RSNA inhibition nor the diuretic and natriuretic responses to
volume loading correlated with arterial pressure in backcross
populations from SHRxWKY-F1-hybrids and WKY that
The assessment of sympathetic activity in animals and
humans invariably includes some kind of manipulation
which may be associated with mental stress. Differences
in so-called ‘‘baseline’’ sympathetic activity between hypertensive and normotensive subjects may therefore partly
reflect a differential responsiveness to mental stress. While
this can be a problem with certain experiments, mental stress
is part of daily life and the responsiveness to stress may be
relevant for the pathogenesis of arterial hypertension.
It is well established that SHR respond with greater
increases of plasma catecholamine concentrations and renal
as well as adrenal sympathetic nerve activity to mental
stressors than WKY. The traits hyperactivity and hyperreactivity to mental stress have been genetically separated
from hypertension in inbred lines derived from SHR and
WKY [59] indicating that elevated neurohumoral reactivity
to stress is not a prerequisite for the development of hypertension in SHR. The precise role of renal sympathetic nerves
in the pathophysiology of hypertension in the new inbred
line which is hypertensive but not hyperactive [59] has not
been investigated.
On the other hand, mental stress can induce hypertension
in borderline hypertensive rats (F1-hybrids derived from
female SHR and male WKY) and stress-induced hypertension can be prevented by renal denervation (reviewed in Ref.
[2]). In a backcross population derived from borderline
hypertensive rats and WKY kept on a high salt diet a positive
correlation between arterial pressure and the extent of RSNA
O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
increase in response to air jet stress was observed [60],
suggesting that increased responsiveness of RSNA to stress
may play a major role in this form of hypertension.
Intermittently elevated plasma and tissue catecholamine
levels as they may occur during mental stress may have
effects on the cardiovascular system that last well beyond
the acute situation. Thus, in a study in normotensive rats
blood pressure increased during systemic infusion of the
a1-adrenoreceptor agonist, phenylephrine, and returned to
normal when the infusion was stopped [61]. When phenylephrine-pretreated animals were exposed to a high salt
diet later in life they developed hypertension associated
with elevated blood pressure variability, increased urinary
protein excretion and tubulointerstitial damage [61]. These
experimental findings demonstrate that stress-induced catecholamine surges may enhance the propensity to develop
renal damage and arterial hypertension in response to
environmental factors such as increased sodium chloride
intake.
There is evidence from clinical studies that the ability to
autoregulate GFR during mental stress-induced elevations in
arterial pressure may be reduced in hypertensive patients. In
young borderline hypertensive humans mental stress caused a
rise in GFR by 10 F 6 ml/min per 1.73 m2 compared to 6 F 7
ml/min per 1.73 m2 in normotensive controls [62]. This was
associated with a similar reduction of renal plasma flow
(RPF) in both groups but with slightly higher plasma renin
activity in borderline hypertensive subjects [62]. A study in
elderly patients with isolated systolic hypertension [63] also
demonstrated an increase in GFR in response to mental stress
in hypertensives which was not seen in normotensive controls. In contrast to the study performed in young borderline
hypertensive subjects [62] the rise in GFR observed in elderly
patients was accompanied by an elevation in RPF [63]. In
another study [64] hypertensive subjects showed a similar
increase in arterial pressure but a lower rise in urinary sodium
excretion in response to mental stress than normotensive
subjects. In the same study [64] changes in GFR, plasma
angiotensin II concentration and renal sodium excretion in
response to mental stress were not different between normotensive subjects with and without a family history of hypertension, suggesting that hypertension and alterations in renal
hemodynamic and excretory responses to mental stress may
develop concomitantly. The altered renal responses to mental
stress may be indicative of pathologic changes in preglomerular vessel function which cause a compromised myogenic
response. This in turn may exacerbate the development of
glomerular damage due to elevations in glomerular capillary
pressure.
4. Renovascular hypertension and angiotensin II
There is evidence for widespread sympathetic activation
in renovascular hypertension. In rats both one-kidney, oneclip and two-kidney, one-clip hypertension are associated
243
with elevated plasma norepinephrine levels [65]. In twokidney, two-clip hypertensive dogs, plasma catecholamine
concentrations and norepinephrine spillover rate were significantly increased [66]. Based on MSNA recordings and
measurements of total body norepinephrine spillover several [67 – 69] but not all studies [27] found elevated sympathetic activity in patients with renovascular hypertension.
Direct evidence for elevated RSNA in renovascular hypertension is limited. This is in part due to technical difficulties
of measuring RSNA in experimental clip-induced renovascular hypertension. A study in two-kidney, one-clip hypertensive rabbits [70] suggests that RSNA to the non-clipped
kidney is reduced. In keeping with these results plasma
epinephrine and norepinephrine concentrations were higher
in renal venous blood from the stenotic than the nonstenotic kidney in patients with renovascular hypertension
[71]. The higher renal venous plasma catecholamine concentrations may be due to activation of RSNA to the
stenotic kidney [71].
Alterations of arterial baroreflex regulation of sympathetic
activity are also present in renovascular hypertension. Experimental data suggest that these reflex alterations may change
with the course of the disease. In two-kidney, one-clip
hypertensive rabbits the gain and range of arterial baroreflex-induced changes in RSNA to the non-clipped kidney was
reduced, 3 weeks after renal artery clipping, but tended to
normalize in the chronic phase of renovascular hypertension
[70]. In chronic human renovascular hypertension the arterial
baroreflex regulation of MSNA was reset to higher arterial
pressure levels but was unchanged with regard to its range
and sensitivity compared to normotensive subjects [27].
Circulating angiotensin II may contribute to elevated
sympathetic activity in renovascular hypertension by its
actions on the central nervous system (reviewed in Ref.
[72]) or by activation of postganglionic sympathetic neurons
[73,74]. In addition, elevated renal angiotensin II levels may
contribute to altered regulation or stimulation of RSNA in
renovascular hypertension by suppression of inhibitory renorenal reflexes as has been recently shown in chronic heart
failure rats [75]. The contribution of angiotensin II to elevated
sympathetic nerve activity in renovascular hypertension is
supported by experimental pharmacological interventions.
Thus, acute reductions of mean arterial pressure in twokidney, one-clip hypertensive rats with the angiotensin II
AT1 receptor blocker, losartan, or the ACE inhibitor, lisinopril, for 120 min caused only transient reflex increases in
splanchnic sympathetic nerve activity [76], whereas similar
arterial pressure reductions with sodium nitroprusside caused
a sustained increase in splanchnic nerve activity [76].
The effects of the renin –angiotensin system on sympathetic activity are also evident from data in renovascular hypertensive patients. Thus, the successful dilation of
a stenotic renal artery lowers not only plasma renin
activity but also MSNA [67]. Furthermore, plasma renin
activity and plasma angiotensin II levels correlated well
with MSNA and total body norepinephrine spillover [68].
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O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
Similar to experimental data [76] acute arterial pressure
reduction by 15 mm Hg with dihydralazine but not with
the ACE inhibitor, enalaprilat, elicited increased sympathetic activity in patients with renovascular hypertension
as evidenced by a 50% rise in total body norepinephrine
spillover and a 15% increase in peroneal sympathetic
nerve activity [77]. In contrast, enalaprilat but not dihydralazine increased renal norepinephrine spillover by 40%
in renovascular hypertensive patients [77]. These data are
difficult to interpret since norepinephrine spillover was
measured from both kidneys together [77] and the reason
for elevated renal norepinephrine spillover after ACE
inhibition is not clear. Overall, activation of the plasma
renin – angiotensin system contributes to a generalized
sympathetic activation in renovascular hypertension. If
angiotensin II contributes to apparent differences in efferent RSNA between the stenotic and the non-stenotic
kidney as well as to abnormalities in reno-renal reflex
function requires further investigation.
5. End-stage renal disease
End-stage renal disease may develop as a consequence of
chronic hypertension irrespective of its aetiology and contributes to elevated mortality in hypertensive patients. Evidence is accumulating that activation of the sympathetic
nervous system occurs in this condition at least in part as a
consequence of chronic activation of sympathoexcitatory
inputs through renal afferent nerves.
In keeping with this notion, rats with 5/6 nephrectomy
developed hypertension which was accompanied by elevated norepinephrine turnover rates in several brain areas and
which was prevented by renal afferent denervation (dorsal
rhizotomy) [78]. Rats with an acute phenol-induced renal
lesion also showed increases in arterial pressure, RSNA and
norepinephrine turnover rate in several brain nuclei which
were antagonized by angiotensin II AT1 receptor blockade
[79]. Furthermore, in mice acute administration of cyclosporine A elicited arterial hypertension accompanied by
increases in both afferent and efferent renal nerve activity
[80]. However, in synapsin knock-out mice the cyclosporine A-induced increases in arterial pressure and RSNA were
greatly attenuated and the cyclosporine A-induced activation of afferent renal nerve activity was abolished [80].
These findings indicate that a reflex activation of sympathetic nerve activity involving renal afferent nerves contributes to acute cyclosporine A-induced hypertension [80].
On the other hand, chronic cyclosporine A-induced nephropathy was not associated with hypertension in uninephrectomized Sprague – Dawley rats and renal denervation
had no effect on the development of renal damage [81].
Similar to the above mentioned experimental data,
haemodialysis patients with both native kidneys showed
higher arterial pressure, increased MSNA and elevated
peripheral vascular resistance compared to bilaterally
nephrectomized patients [82]. Furthermore, renal transplanted patients with both native kidneys showed higher
MSNA than patients in whom the diseased kidneys had
been removed [83]. Recently, elevated plasma neuropeptide Y levels, plasma norepinephrine concentrations and
arterial pressure have been demonstrated to be associated
with left ventricular hypertrophy in patients with endstage renal disease [84].
Together, experimental findings and data obtained from
studies in humans indicate that changes within the failing
kidney such as inflammation and scarring can chronically
activate renal afferent nerves which in turn causes sympathetic activation and thus contributes to worsening of
arterial hypertension.
6. Conclusion
Inappropriately high levels of sympathetic activity
contribute to both primary (essential) and secondary forms
of hypertension. Experimental studies provide evidence
that altered interactions between the sympathetic nervous
system and the kidney during ontogeny can be involved
in the pathogenesis of primary hypertension. Further
mechanisms leading to elevated sympathetic tone in
primary hypertension include elevated central sympathetic
drive and exaggerated responsiveness to mental stress as
well as inherited reductions in somatic and visceral
sensory receptor sensitivity. Subtle pathologic changes in
the kidney which develop during mild stages of essential
hypertension may increase its sensitivity to rises in
sympathetic activity as occur during daily life and thus
accelerate the rise in arterial pressure. Serious pathological
changes within the kidney as occur in end-stage renal
disease directly activate the sympathetic nervous system
via elevated afferent renal nerve activity.
Experimental studies going beyond comparisons of
inbred genetically hypertensive and normotensive rodent
strains by using segregating populations or recombinant
inbred strains [54,85] will continue to contribute to our
understanding of the complex relationship between the
sympathetic nervous system and renal mechanisms in the
pathogenesis of hypertension. In addition to the rapidly
developing tools of molecular biology this requires high
quality and high throughput physiological techniques that
allow for the precise characterization of integrated systems.
Recent studies in carefully characterized human study
populations show that elevated renal and muscle sympathetic nerve activity is not unequivocally associated with
essential hypertension. Prospective clinical studies which
investigate a broader array of physiological functions will
help to define specific phenotypes associated with elevated
sympathetic activity and elevated renal sympathetic activity in particular. Follow up of such study populations will
help to define conditions under which elevated sympathetic
activity acts as a causal factor for hypertension.
O. Grisk, R. Rettig / Cardiovascular Research 61 (2004) 238–246
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