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Causes and Consequences of Increased Sympathetic Activity
in Renal Disease
Jaap A. Joles, Hein A. Koomans
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Abstract—Much evidence indicates increased sympathetic nervous activity (SNA) in renal disease. Renal ischemia is
probably a primary event leading to increased SNA. Increased SNA often occurs in association with hypertension.
However, the deleterious effect of increased SNA on the diseased kidney is not only caused by hypertension. Another
characteristic of renal disease is unbalanced nitric oxide (NO) and angiotensin (Ang) activity. Increased SNA in renal
disease may be sustained because a state of NO–Ang II unbalance is also present in the hypothalamus. Very few studies
have directly compared the efficacy of adrenergic blockade with other renoprotective measures. Third-generation
␤-blockers seem to have more protective effects than traditional ␤-blockers, possibly via stimulation of NO release.
Although it has been extensively documented that muscle SNA is increased in chronic renal failure, data on renal SNA
and cardiac SNA are not available for these patients before end-stage renal disease. It is also unknown whether
additional treatment with third-generation ␤-blockers can delay the progression of renal injury and prevent cardiac
injury in chronic renal failure more efficiently than conventional treatment with angiotensin-converting enzyme
inhibitors only. (Hypertension. 2004;43:699-706.)
Key Words: renal disease 䡲 antihypertensive agents 䡲 hypertension 䡲 diabetic nephropathy
䡲 sympathetic nervous system
I
In the clinical setting, however, the intracellular domain is
not yet accessible and gene therapy lies beyond the horizon.
Hence, the focus of much research, both clinical and experimental renal disease, is directed toward manipulation of
extracellular pathways. In this review, we focus on the role of
the sympathetic nervous system (SNS), which is activated in
subjects with renal disease.6 First, we briefly review potential
mechanisms that could be responsible for SNS stimulation in
renal disease. Then, we summarize the evidence that SNS
stimulation contributes to progression of renal disease. Mortality caused by cardiovascular disease is more than 3-times
higher in subjects with ESRD than in subjects with normal
renal function.7 Hence, we also review recent studies that
support a role for the SNS in the myocardial changes that are
inherent to uremia.
t is well known that irrespective of the primary cause of
renal injury, chronic renal disease often leads to renal
fibrosis and end-stage renal disease (ESRD). Delaying the
onset of renal replacement therapy is of utmost importance,
both medically and economically.1 Many quite different
interventions (dietary protein or phosphate restriction, inhibition of the renin-angiotensin system [RAS], endothelin
receptor antagonists, aldosterone antagonists, antioxidants,
renal denervation, HMG-CoA reductase inhibitors, etc) have
been shown to considerably slow this process in experimental
models. In fact, if these were all discrete pathways, then
combining such interventions would provide additive protective effects that would exceed the loss of function. Clearly,
this is not the case, suggesting that parallel extracellular
pathways converge on common intracellular signaling molecules, which in turn activate a limited number of transcription
factors that turn on excessive matrix synthesis. Recent studies
using modulation of intracellular signaling pathways, eg, by
gene transfer of Smad 7,2 or inhibition of transcription factors
with antisense technology3 show marked reduction of fibrosis
in robust models such as unilateral ureteral obstruction.
Another pathway that is gaining increasing attention is the
independent role of proteinuria in causing interstitial inflammation and ultimately fibrosis.4 Such inflammation causes
cytokine release and consequent monocyte influx. Preventing
this monocyte influx by anti-monocyte chemoattractant protein (MCP)-1 gene therapy5 also reduces injury.
What Stimulates the SNS in Renal Disease?
In the later stages of chronic renal disease, when renal
clearance is substantially decreased, renal catabolism of
peptides and low-molecular-weight proteins will decrease.
One such peptide is leptin, a peptide produced mainly in
adipose tissue, that decreases food intake and increases
energy expenditure. The latter is mediated by an increase in
SNS activity.8 Hyperleptinemia is common in ESRD.9 It has
been postulated that increased SNS activity associated with
hyperleptinemia may contribute to hypertension in ESRD10 as
Received October 10, 2003; first decision November 5, 2003; revision accepted February 3, 2004.
From the Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands.
Correspondence to Dr Jaap A. Joles, Department of Nephrology and Hypertension (Room F03.226), University Medical Center, Heidelberglaan 100,
P.O. Box 85500, 3508 GA Utrecht, The Netherlands. E-mail [email protected]
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000121881.77212.b1
699
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Hypertension
April 2004
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it does in obesity.11 Accumulation of endogenous nitric oxide
synthase (NOS) inhibitors in chronic renal failure (CRF) such
as asymmetric dimethyl arginine could potentially directly
increase SNS activity by inhibiting cerebral NO production.
However, this is not likely because the levels are very low.12
Moreover, direct effects of uremia cannot be the whole story,
because SNS activity is already increased at earlier stages when
renal function is not or only slightly impaired13 and sympathetic
hyperactivity remains after correction of uremia by renal transplantation.14 Increased SNS activity in the presence of normal
renal function is also sometimes found in the nephrotic syndrome, in which central cardiovascular stimulation is thought to
play an important role in stimulating efferent renal sympathetic
nervous activity (RSNA).15 However, judging by noradrenaline
levels, this association only appears to be present in conjunction
with hypovolemic symptoms.16
Renal ischemia is probably an important primary event
leading to increased SNS activity. This was observed experimentally with acute renal artery stenosis.17 Restoration of
renal perfusion in humans with renovascular hypertension
reduces muscle sympathetic nerve activity (MSNA) to control levels along with normalization of blood pressure.18
Increased SNS activity has also been observed in hypertensive subjects with polycystic kidney disease and normal renal
function.13 It is conceivable that renal cysts cause localized
intrarenal ischemia, which in turn stimulates ␣2 adrenoceptors. Campese’s group has shown in rats that unilateral
intrarenal injection of a small quantity of phenol induces
hypertension that is associated with increased RSNA.19 Increased norepinephrine content of the posterior hypothalamic
nuclei is present in the 5/6-nephrectomy model.20 Importantly, in the 5/6-nephrectomy model, it was also shown that
central sympathetic activation could be dampened by central
production of NO from neuronal NOS.20 Intraventricular
administration of angiotensin (Ang) II also directly increases
central sympathetic output.21
Unbalanced NO Versus Angiotensin and
Sympathetic Activity in Renal Disease
Within the kidney, NOS activity progressively decreases in
CRF induced by ablation, as does urinary nitrite plus nitrate
excretion.22 Similar findings have been discovered in
immune-mediated glomerulonephritis.23 Moreover, proteinuria and renal injury induced by hypercholesterolemia are
also accompanied by a reduction in renal NOS activity.24 In
both ablation and hypercholesterolemia, proteinuria and injury are partially or wholly prevented by molsidomine, a NO
donor.24,25 Angiotensin-converting enzyme (ACE) inhibition
or AT-1 antagonism effectively reduces renal injury in the
ablation and NOS inhibition models,26 and this is also the
case for renal injury associated with hypercholesterolemia.27
Thus, a characteristic of renal disease is unbalanced NO and
Ang activity.28 However, this does not necessarily imply that
tissue Ang II is actually increased, but rather that it is high in
relation to the protection offered by NO activity. Indeed, Ang
II levels were neither increased in the intact portion of the
remnant kidney (away from the infarct scar)29 nor in the
whole kidney during NOS inhibition with a high dose of
NG-nitro-L-arginine (L-NNA), at least not before the develop-
ment of extensive injury and scarring.30 Increased SNS
activity in renal disease may be sustained because a state of
NO-Ang II imbalance is also present in the hypothalamus.20,21
Enhanced SNS activity appears to be a direct effect of
primary NO deficiency, even before renal insufficiency.
Circulating catecholamines, particularly epinephrine, levels
were increased several-fold after chronic NG-nitro-L-arginine
methylester (L-NAME) treatment.31 Intracisternal NG-monomethyl-L-arginine (L-NMMA) administration resulted in a
mild pressor response but in marked stimulation of RSNA.32
Recently, it was shown that the acute central antihypertensive
action of clonidine, an ␣2-adrenergic agonist, is caused by the
release of NO in the nucleus tractus solitarii (NTS).33 Thus,
the marked antihypertensive effect of chronic clonidine administration observed in the intrarenal phenol model by Ye et
al was possibly not only caused by maintenance of intracerebral nNOS mRNA19 but also caused by direct stimulation of
NO release in the brain.
SNS activity plays an important role in the genesis of
hypertension in NO deficiency. Renal denervation can prevent L-NAME hypertension.34 Similarly, adrenergic blockade
can prevent hypertension when NO deficiency is induced in
pregnant rats35 and in diabetic rats.36
Catecholamines are potent stimulators of platelet aggregation.37 Conversely, chronic NO deficiency induced intraglomerular platelet aggregation and glomerular injury, which
was ameliorated by renal denervation.38 Moreover, increased
SNS activity may in fact aggravate the NO deficiency
induced by L-NAME, because the ␣1-adrenoceptor blocker,
doxazosin, increased the nitrite production of kidney tissue of
L-NAME–treated rats.39 However, this may be caused by the
partial correction of hypertension, because a calcium channel
antagonist and an ACE-inhibitor shared this effect on nitrite
production. Interestingly, renal nitrite production was increased above control levels when L-NAME–induced hypertension was treated with either the ␣1-adrenoceptor blocker
or the ACE inhibitor,39 suggesting that even under control
conditions both RSNA and intrarenal Ang II suppress renal
NO production. Thus once renal insufficiency starts to
develop, the resulting depression of renal NO synthesis and
enhancement of RSNA and the intrarenal RAS start to
reinforce each other in an ominous dance. Neutralization of
any one of these factors reduces progression of renal injury.
For example, in renal ablation renal function and structure
can be preserved by a NO donor,25 ACE inhibition, or AT-1
antagonism,26 or by ␣ and ␤ blockade.40 Moreover, even
though this model is classically regarded as being hemodynamically driven, protection by the lymphocyte inhibitor,
mycophenolate mofetil, indicates that inflammatory factors
play a key role in scarring.41 Combining hemodynamic and
non-hemodynamic interventions may provide somewhat better protection.41 The challenge is to identify and target
different multiple upstream pathways to halt activation of the
common downstream pathway.
How Does SNS Stimulation Contribute to
Progression of Renal Disease?
Is Hypertension Always Involved?
The deleterious effect of increased SNS activity on the
diseased kidney is not only caused by hypertension. In fact,
Joles and Koomans
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infusion of noradrenaline for 1 week did not induce proteinuria or decrease glomerular filtration rate (GFR), in contrast
to Ang II, despite similar development of severe hypertension.42 Note that longer periods of noradrenaline infusion,
even at a lower doses and, hence, blood pressure, do cause
vascular43 and renal injury44 vide infra. Moxonidine, an
I1-imidazoline agonist that inhibits the release of noradrenaline both in the kidney and in the brain,45 reduced glomerulosclerosis and albuminuria without changing blood pressure
in the subtotal nephrectomy model.46 Furthermore, in subtotally nephrectomized rats, subantihypertensive doses of ␣ and
␤ blockade, and particularly their combination, also reduced
progression of renal disease.40 Similarly, in extremely hypertensive stroke-prone spontaneously hypertensive rats (SHR)
on a high-fat, high-sodium diet, ␤ blockade increased survival and reduced glomerular, tubulointerstitial, and intrarenal vascular injury without any effect on systolic blood
pressure.47,48 This contrasts with the renoprotective effects of
ACE inhibition and aldosterone blockade in salt-loaded
stroke-prone SHR and of ACE-inhibition and AT-1–receptor
blockade in renal ablation that were consistently bloodpressure dependent.49,50 Note in the studies by Amann’s
group and in those of Bidani’s group that blood pressure was
measured continuously in conscious unrestrained animals
using telemetry.40,46,49,50 Thus renal protection by blockade of
the RAS or by reduction of SNS activity may not follow
identical pathways. This supports the notion that complementary combinations may have beneficial effects. Surprisingly,
little information is available on the effects of adrenergic
blockade in models of renal injury not associated with
hypertension, although it has been documented that in experimental nephrotic syndrome RSNA is increased.15
Sympathetic Hyperactivity: Mainly Vascular and
Glomerular Effects
Prolonged SNS hyperactivity can induce changes in intrarenal blood vessels. Catecholamines induce proliferation of
smooth muscle cells and adventitial fibroblasts in the vascular
wall.43,51 ␣1-Adrenoceptors mediate these effects.51 In vivo,
however, such effects are difficult to prove because the
simultaneous hemodynamic effects also have trophic effects.
However, suffusion of rat carotid arteries for 2 weeks with
noradrenaline at ⬇1000-times below the threshold for altering arterial pressure clearly caused hypertrophy.43 Interestingly, a new hypothesis relating peritubular capillary rarefaction to salt-sensitive hypertension52 was initially supported by
observations in rats infused with phenylephrine for 8 weeks.44
However, subsequently this has been observed in many other
primary models of hypertensive renal injury,52 so this cannot
be viewed as a specific adrenergic effect.
Perivascular nerves in the adventitia release ATP with
noradrenaline and neuropeptide Y from sympathetic nerves to
act at smooth muscle P2X purinoceptors resulting in vasoconstriction.53 In preglomerular vessels, ATP and ADP stimulate P2 receptors and cause vasoconstriction by opening
calcium channels, whereas AMP and adenosine stimulate P1
receptors (adenosine A1 receptors) and cause relaxation by
increasing cAMP formation.54 Although adrenergic fibers do
not penetrate the glomerulus,55 podocytes56 have adrenocep-
Sympathetic Activity in Renal Disease
701
tors, and all glomerular cell types have purinoceptors.57 In
contrast to the preglomerular vessels in which ATP causes
constriction,54 ATP efflux from endothelial cells in isolated
glomeruli stimulates P2Y purinoceptor-mediated NO release
and causes dilation of glomerular capillaries.58 This microvascular endothelial ATP release is potently reinforced by
third-generation ␤-blockers.58 These apparently conflicting
actions of extracellular ATP are possible because extracellular ATPase limits the half-life of extracellular ATP to 0.2
seconds.57
Dissecting the exact mechanism by which sympathetic
activity damages the glomerulus independently of Ang II is
not trivial. Podocyte injury is a pivotal step in the development of glomerulosclerosis, and an early event is probably
calcium influx, constriction, and hence decreased glomerular
permselectivity.56 Adrenergic and purinergic receptors appear
to be present on podocytes, because adrenergic and purinergic
agonists induced calcium influx.56 Podocytes also have Ang
II receptors, and Ang II can also induce calcium influx in
podocytes ex vivo.56 Thus direct effects of both the RAS and
the SNS may lead to podocyte constriction and proteinuria,
independently of their hemodynamic effects. Interestingly, in
a 2-week experiment with dietary hypercholesterolemia, ie,
before the development of proteinuria, we observed a decrease in renal NOS activity and protective effects of losartan
on podocyte activation without a significant decrease in blood
pressure.59 Similarly, Amann et al observed podocyte protection with adrenergic blockade without a change in blood
pressure in the subtotal nephrectomy model.40
Secondary Tubulointerstitial Changes
It is well known that the tubular epithelium is densely
innervated and well endowed with both adrenergic55 and
purinergic57 receptors. However, in contrast to Ang II that
directly stimulates proliferation, apoptosis and collagen synthesis via its receptors on the tubular epithelium,60 adrenergic
and purinergic receptors do not appear to be directly involved
in the characteristic tubulointerstitial changes of chronic renal
disease. Catecholamine infusion, in contrast to Ang II, did not
stimulate tubular epithelial or interstitial apoptosis or proliferation.61 The overriding tubulotoxic effects of proteinuria4
preclude dissection of a sympathetic contribution to interstitial fibrosis in most models.
Adrenergic Blockade in Different Models of
Renal Disease
␤-Adrenergic Receptor Blockade
There are several studies showing renal protection by
␤-adrenergic receptor blockade in 5/6 nephrectomy.40,62– 65
Renal protection by ␤-blockade has also been observed in
NOS inhibition66 – 68 and in stroke-prone SHR on high-salt
intake.47 Experimental studies of renal injury that evaluated
adrenergic blockade are listed in Table 1. Very few studies
have directly compared the efficacy of adrenergic blockade
with other renoprotective measures. In the study by Brooks et
al,65 very similar protection was found for carvedilol and
captopril. There may also be substantial differences between
different ␤-blocking drugs. Third-generation ␤-blockers,
702
Hypertension
April 2004
TABLE 1. Effects of Renal Denervation or Pharmacological Blockade of the Sympathetic Nervous System on Blood Pressure and
Renal Injury in Different Models of Renal Disease
Model
Treatment
Study
Length
Glomerular
Blood Filtration
Glomerular Tubulo-int. Vascular
Pressure
Rate
UalbV UprotV Injury
Injury
Injury Reference
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5/6 NX excision
Renal denervation
12 wk
7
7
2
2
2
2
75
5/6 NX excision
Moxonidine 1.5 mg/kg per day
12 wk
7
7
2
2
7
2
46
5/6 NX excision
Phenoxybenzamine 5 mg/kg per day
12 wk
7
7
2
2
2
2
40
5/6 NX excision
Metoprolol 150 mg/kg per day
12 wk
7
7
2
2
2
2
40
5/6 NX excision
Phenoxybenzamine⫹Metoprolol
12 wk
7
7
2
22
22
22
40
5/6 NX excision
Nipradilol 10 or 15 mg/kg per day
12 wk
2
1
2
2
N/A
N/A
64
5/6 NX excision
Propanolol 50 mg/kg per day
12 wk
2
1
2
7
N/A
N/A
64
5/6 NX excision⫹L-NAME
6 mg/kg per day
Nipradilol 10 mg/kg per day
12 wk
2
1/7
7
2/7
N/A
N/A
64
5/6 NX excision⫹L-NAME
6 mg/kg per day
Propanolol 50 mg/kg per day
12 wk
2
7
7
7
N/A
N/A
64
5/6 NX excision
Carvedilol 30 mg/kg per day
11 wk
2
1
2
2
N/A
N/A
63
5/6 NX excision
Propanolol 30 mg/kg per day
11 wk
2
1
2
7
N/A
N/A
63
98
5/6 NX infarction
Renal denervation
6 wk
2
1
N/A
2
N/A
N/A
5/6 NX infarction
Carvedilol 55 mg/kg per day
6 wk
2
1
N/A
2
2
N/A
65
5/6 NX infarction
Carvedilol 5 or 10 mg/kg per day
11 wk
7/2
1
2
2
2
N/A
62
5/6 NX infarction
Carvedilol 20 mg/kg per day
11 wk
2
1
22
22
22
N/A
62
Obese SHR
Moxonidine 8 mg/kg per day
13 wk
2
N/A
2
N/A
N/A
N/A
88
SHR/N-cp diabetes
Doxazosin 40 mg/kg per day*
16 wk
2
N/A
2
2
N/A
N/A
73
STZ diabetes
Doxazosin 30 mg/kg per day*
20 wk
2
N/A
22
7
N/A
N/A
82
Renal denervation
4 wk
2
N/A
2
N/A.
N/A
N/A
34
L-NAME
70 mg/kg per day
L-NAME
80 mg/kg per day
Renal denervation
4 wk
N/A
N/A
2
22
2
N/A
38
L-NAME
60 mg/kg per day
Doxazosin 10 mg/kg per day
10 wk, treated
last 4 wk
2
N/A
N/A
2
N/A
N/A
39
L-NAME
5 mg/kg per day*
Doxazosin 30 mg/kg per day
12 wk, treated
last 6 wk
2
7
2
N/A
N/A
N/A
66
L-NAME
5 mg/kg per day*
Metoprolol 350 mg/kg per day
12 wk, treated
last 6 wk
22
7
22
N/A
N/A
N/A
66
L-NAME
35 mg/kg per day
Prazosin 5 mg/kg per day*
6 wk
2
7
22
22
22
22
68
Prazosin 5 mg/kg per day*
6 wk
2
7
22
22
22
22
68
SHR⫹L-NAME
10 mg/kg per day*
Nipradilol 20 mg/kg per day
3 wk
2
1
N/A
2
N/A
N/A
67
Aging SHRSP
Moxonidine 8 mg/kg per day
3 month
2
N/A
N/A
2
2
2
99
L-NAME⫹DOCA
SHRSP⫹high salt
Carvedilol 200 mg/kg per day*
18 wk (survival)
7
7
N/A
2
2
2
47
SHRSP⫹high salt
Propanolol 200 mg/kg per day*
18 wk (survival)
7
7
N/A
2
2
2
47
SHRSP⫹high salt
Carvedilol 200 mg/kg per day*
7 wk
7
1
2
2
2
2
48
Pregnancy⫹L-NAME
10 mg/kg per day
Methyldopa 400 mg/kg per day
D11 to term
2
1
2
N/A
N/A
N/A
35
Carvedilol 2 mg/kg per day
intraperitoneal
8d
N/A
1
N/A
N/A
22
N/A
69
Gentamicin acute renal failure
N/A indicates not available; tubulo-int., tubulointerstitial; NX, nephrectomy; 1, increased; 2, decreased; 7, unchanged (all in comparison to the levels found in
the non-treated model).
Abbreviations are defined in the text.
*Calculated from intake and body weight.
such as carvedilol and nebivolol, seem to have more protective effects than traditional ␤-blockers,47,63 possibly via stimulation of NO release.58 In fact, carvedilol is even protective
in acute renal failure after gentamicin.69 Third-generation
␤-blockers are now rapidly becoming the drug of choice in
heart failure in the general population.70 However, their use in
patients with advanced renal failure who experience myocardial infarction is grossly neglected.71 Hopefully, the marked
improvement of heart function and survival of dialysis
patients with heart failure achieved by carvedilol72 will
improve this treatment deficit. The important question is
whether additional treatment with these drugs can delay the
Joles and Koomans
progression of renal injury and prevent cardiac injury in
chronic renal failure more efficiently than conventional treatment with ACE inhibitors only. To our knowledge, not a
single experimental study is available that addresses this
question.
␣-Adrenergic Receptor Blockade
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Renal protection by ␣-adrenergic receptor blockade has also
been observed in the 5/6-nephrectomy model,40 in NOS
inhibition,39,66,68 and in type 2 diabetes in corpulent SHR.73
Combining ␣-adrenergic blockade (doxazosin) with ACE
inhibition only provided slightly better protection (ie, less
mesangial expansion) than single-drug treatment in spontaneous type 2 diabetes.73 However, the use of ␣-adrenergic
blockade has been superseded by the findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT) study in which the most recent
analysis conclusively shows a higher risk of stroke and
combined cardiovascular disease in patients treated with
doxazosin than in those using the diuretic chlorthalidone.74
Inclusion criteria for the ALLHAT study were age (older than
55 years), hypertension, and at least one additional risk factor.
Note that renal disease was not a recognized risk factor, and
⬇36% of the patients had type 2 diabetes;74 thus, the results
of this study cannot be directly extrapolated to chronic renal
disease.
␣ Plus ␤-Adrenergic Receptor Blockade
A combination of ␣ blockade and ␤ blockade (phenoxybenzamine plus metoprolol) aimed at preventing both ␣-adrenergic–mediated ATP release and ␤-adrenergic–mediated renin release was more effective in reducing renal damage
(glomerular, tubulointerstitial, and vascular) in the subtotal
nephrectomy model than ␣ blockade only.40 Similar beneficial effects were observed in this model with the central
sympatholytic agent moxonidine46 and renal denervation.75 A
recent comparative study in patients with advanced CRF
showed that moxonidine superimposed on some form of RAS
inhibition delayed loss of renal function over a 24-week
period, whereas superimposing nitrendipine did not.76 However, as pointed out by Laverman and Remuzzi, this observation needs a follow-up because at the start of the trial, the
albumin excretion was substantially lower (1.3 versus 1.9
g/d) in the group subsequently treated with moxonidine.77
Diabetes and Obesity
Diabetes triggers mechanisms that in parallel enhance and
suppress NO bioavailability in the kidney. In the early phases
of diabetic nephropathy, the balance between these opposing
forces appears to be shifted toward increased NO, whereas in
a later phase, factors that suppress NO bioavailability prevail.78 A similar situation may apply to SNS activity. MSNA
is typically reduced in insulin-dependent diabetes mellitus
patients without diabetic complications,79 and RSNA is decreased after 2 weeks in normotensive streptozotocin (STZ)induced diabetes in rats.80 Indeed, Matsuoka found that renal
denervation before induction of diabetes with STZ enhanced
albuminuria.81 At a later stage, however, sympathetic nerve
activity is clearly deleterious, because when ␣-adrenergic
Sympathetic Activity in Renal Disease
703
blockade was started 1 week after STZ, albuminuria decreased.82 Normotensive type 1 diabetic patients who had had
diabetes for ⬎15 years showed a reduction in microalbuminuria after treatment with a dose of moxonidine that did not
affect blood pressure.83 However, when diabetic nephropathy
is allowed to progress, renal denervation is no longer able to
decrease albumin and transforming growth factor (TGF)-␤
excretion.84 In meta-analyses of studies exclusively directed
at diabetes, ACE-inhibition was approximately twice as
effective as diuretics and/or ␤-blockers in reducing proteinuria85 and cardiovascular events.86 The only exception was
the United Kingdom Prospective Diabetes Study (UKPDS),
which did not show any difference and involved 758 of 2180
patients in the meta-analysis by Pahor et al.86 Thus, in the
race to save diabetic patients from renal and cardiovascular
disease, the conventional ␤-blockers seem to have been
beaten by the ACE inhibitors. However, in the next run-off,
third-generation ␤-blockers have good chances.
A common disorder that is closely linked to diabetes is
obesity. Obesity is also associated with microalbuminuria.87
As mentioned, doxazosin reduced albuminuria in corpulent
SHR,73 and proteinuria was also lower in obese SHR treated
with moxonidine.88 Interestingly, in the latter study the
antihypertensive and renoprotective actions of moxonidine
were accompanied by improvement of glucose tolerance and
insulin sensitivity.88 Although renal SNS activity is clearly
increased in normotensive and in hypertensive obesity,89 an
effect of adrenergic blockade on microalbuminuria has yet to
be shown in obesity.
SNS Stimulation and Cardiac Injury in
Chronic Renal Disease
Experimental Studies
Experimental studies that evaluated effects of adrenergic
blockade on cardiac injury in chronic renal disease are listed
in Table 2. Although most of the experimental studies in
which blood pressure is decreased by sympathetic inhibition
also found a decrease in left ventricular hypertrophy,68 this
cannot be viewed as a specific effect. In renal ablation
studies, both moxonidine90 and carvedilol62 reduced myocardial interstitial volume and restored the abnormal myocardial
capillary density. Similar findings were documented in aging
stroke-prone SHR.91 Because blood pressure decreased in
these studies, it remains difficult to distinguish a specific
effect of decreased adrenergic action on the heart. However,
in stroke-prone SHR on a high-salt diet, good cardiac92 and
renal47 protection was observed with carvedilol without any
change in blood pressure. In this model, we have previously
found partial reduction of proteinuria and total remission of
cerebral edema for many months after late initiation of ACE
inhibition or AT-1 receptor blockade once injury was present,
despite persistent severe hypertension.93 Thus, part of the
protective action of carvedilol in this model may be caused by
a decrease in tissue Ang II activity in target organs.
Clinical Studies
Cardiac sympathetic nervous activity (CSNA), MSNA, and
RSNA are coordinately increased in essential hypertension
704
Hypertension
April 2004
TABLE 2. Effects of Pharmacological Blockade of the Sympathetic Nervous System on Blood Pressure and Cardiac Injury in Different
Models of Renal Disease
Treatment
Study
Length
Blood
Pressure
Left
Ventricular
Hypertrophy
Arteriolar
Thickening
Capillary
Density
Interstitial
Volume
Inflammation,
Microthrombosis,
and Infarction
Reference
70 mg/kg
Propanolol 100 mg/kg per day*
8 wk
2
2
N/A.
N/A.
N/A.
2
100
70 mg/kg
Atenolol 100 mg/kg
per day*
8 wk
2
2
N/A.
N/A.
N/A.
2
100
35 mg/kg
per day⫹DOCA
Prazosin 5 mg/kg
per day*
6 wk
2
2
N/A.
N/A.
N/A.
N/A.
68
Model
L-NAME
per day*
L-NAME
per day*
L-NAME
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5/6 NX infarction
Carvedilol 5 or 10 mg/kg per day
11 wk
7/2
2
N/A.
2
2
2
62
5/6 NX infarction
Carvedilol 20 mg/kg
per day
11 wk
2
2
N/A.
22
22
2
62
SHRSP⫹high salt
Carvedilol 200 mg/kg per day*
18 wk
(survival)
7
2
2
N/A.
2
22
92
5/6 NX excision
Moxonidine 10 mg/kg per day
8 wk
2
2
7/2
2
2
N/A.
90
Moxonidine 8 mg/kg
per day
3 month
2
2
2
2
2
22
91, 99
Aging SHRSP
Abbreviations are defined in the text.
N/A indicates not available; 1, increased; 2, decreased; 7, unchanged (all in comparison to the levels found in the non-treated model).
*Calculated from intake and body weight.
associated with left ventricular (LV) hypertrophy.94 Similarly, CSNA95 and RSNA96 are increased in congestive heart
failure, which provides the theoretical foundation for the
successful use of ␤-blockers in heart failure. Unfortunately,
although it has been extensively documented that MSNA is
increased in CRF,6,13 data on RSNA and CSNA are not
available for these patients before ESRD. The recent report
that carvedilol markedly improves survival in dialysis patients with congestive heart failure72 suggests that at this stage
CSNA is increased, just as it is in the general population.95
Whether sympathetic hyperactivity in CRF specifically contributes to the cardiac damage beyond its effect on blood
pressure has received relatively scant attention considering
the magnitude of the problem in the clinic. However, considering the excellent reduction in LV hypertrophy and hypertension achieved recently in the general population with an
ACE inhibitor plus a selective aldosterone blocker,97 it would
appear logical in predialysis patients to add a third-generation
␤-blocker to such a combination.
Conclusion
Although many experimental and clinical studies in diverse
models of renal disease document renoprotective effects of
␣-blockers and ␤-blockers, it remains unclear how adrenergic
blockade can best be used in chronic renal disease. There are
very few comparative trials. For instance, to date no comparison has been made between the third-generation ␤-blockers
and an AT-1 receptor blocker, whereas there is ample reason
to believe that both agents will also enhance NO activity.
Unbalanced NO versus Ang II and sympathetic activity is
characteristic of renal disease. In this setting, both Ang II and
sympathetic activity become damaging factors for kidney and
heart. Given the overwhelming evidence of renoprotection
and cardioprotection provided by interference with the reninangiotensin-aldosterone system, now is the time to investigate
whether complementary combinations are even more effective in the clinical setting.
Acknowledgment
Sandy van Laar is acknowledged for her expert secretarial assistance.
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Jaap A. Joles and Hein A. Koomans
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Hypertension. 2004;43:699-706; originally published online February 23, 2004;
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