THOROUGH CRITICAL APPRAISAL
JNEPHROL 2009; 22: 000-000
www.sin-italy.org/jnonline – www.jnephrol.com
Guido Grassi1,2,3, Francesca Arenare1, Federico
Pieruzzi1, Gianmaria Brambilla1, Giuseppe Mancia1,2,3
1Department of Clinical Medicine, Prevention and Health
Biotechnology University of Milan-Bicocca, San Gerardo
Hospital, Monza, Milan – Italy
2Center of clinical physiology and hypertension, Milan -
3Auxologico Center Milan - Italy]
Sympathetic activation in cardiovascular and
Ab s t r A c t
Given the importance of adrenergic neural functioning
in cardiovascular control, the hypothesis that an eleva-
tion in sympathetic drive represents a key pathophysi-
ological feature of diseases characterized by an im-
pairment in cardiac or renal function has been long
considered. However, modern approaches to directly
quantify sympathetic nerve ﬁring in humans have only
been possible in the last 2 decades to provide objec-
tive documentation for the hypothesis. This paper will
review the evidence that conditions such as essential
hypertension, congestive heart failure and metabolic
syndrome are all accompanied by an increased sym-
pathetic drive, which is likely in all of them to play a
pathogenetic role. It will then offer examples showing
that sympathetic inﬂuences are directly involved in the
progression of organ damage associated with these
conditions. Finally, evidence will be presented that a
maximum degree of sympathetic activation can be
seen in end-stage renal failure, in which a relationship
between sympathetic activation and clinical outcome
has been documented. This has therapeutic implica-
tions, which involve the need to use treatments that
oppose rather than enhance sympathetic neural acti-
Key words: Hypertension, Renal failure, Sympathetic
activity, Sympathoinhibitory drugs
In t r o d u c t I o n
A series of elegant studies performed during the past 2
decades, both in experimental animal models and in hu-
mans, have consistently shown that the sympathetic nerv-
ous system is activated in a variety of cardiovascular dis-
eases, such as essential hypertension, congestive heart
failure, cardiac arrhythmias, myocardial infarction and
ischemic stroke (1, 2). They have also shown that an activa-
tion of the sympathetic nervous system of similar (or even
greater) magnitude characterizes a number of metabolic
disease including diabetes mellitus, obesity and metabolic
syndrome as well (3). During recent years, evidence has
been provided that a state of adrenergic overdrive may also
characterize patients with chronic renal disease, in whom it
participates in the elevated cardiovascular risk proﬁle char-
acterizing this condition (4, 5).
The present paper will ﬁrst describe the behavior of the
sympathetic nervous system in uncomplicated and com-
plicated hypertension. It will then review the available
evidence regarding the sympathetic abnormalities accom-
panying metabolic disease affecting thermogenesis and
overall energy balance, such as obesity and metabolic syn-
drome. Finally, the neurogenic abnormalities characterizing
chronic renal failure will be brieﬂy discussed, highlighting,
wherever possible, the therapeutic implications as well as
the impact of drug treatment.
Sympathetic activation in hypertension
The available evidence indicates that essential hyperten-
sion often has a neurogenic nature, with documentation of
JN_D_08_00149_GRASSI.indd 190 14-04-2009 15:15:24
JNEPHROL 2009; 22:190-195
increased values of different hemodynamic, neurochemical
and neurophysiological markers of sympathetic cardiovas-
cular drive (6).
Early measurements of the hemodynamic proﬁle of essen-
tial hypertension have shown that in a consistent fraction
of young borderline hypertensive patients, their blood pres-
sure elevation is associated with an increase in cardiac out-
put and heart rate, thereby directly documenting the pres-
ence of a so-called hyperkinetic circulation (7). Interestingly,
when norepinephrine was assessed in these patients, an
increase in its circulating plasma levels was found, sup-
porting the hypothesis that neurogenic mechanisms are
involved in the blood pressure elevation. This hypothesis
has later been conﬁrmed by the results of studies based on
more sophisticated but technically demanding approaches
to investigating human neuroadrenergic function, such as
the microneurographic nerve recording technique and the
radiolabeled norepinephrine approach (6). Through these 2
methodologies it has been possible to clarify that sympa-
thetic neural activation accompanies high blood pressure
states and closely parallels the degree of the blood pres-
sure elevation (8-10). It has also been possible to determine
that the adrenergic overdrive (i) is not detectable in second-
ary hypertensive states such as renovascular hypertension,
Cushing syndrome or primary hyperaldosteronism (10, 11),
(ii) affects different regional vascular districts of key impor-
tance for blood pressure control, such as the cerebral, the
coronary as well as the renal circulation (12) and (iii) partici-
pates not only in the development but also in the progres-
sion of the hypertensive state, favoring the occurrence of
end-organ damage, such as cardiac hypertrophy (13, 14).
Recently, the importance of the sympathetic nervous sys-
tem in the pathophysiology of essential hypertension has
been further strengthened by new evidence. This includes
data showing that (i) white-coat and masked hypertension
(i.e., conditions characterized by an elevation in clinic but
not in ambulatory blood pressure or vice versa, or by an
increase in 24-hour vs. normal clinic blood pressure) are
characterized by an adrenergic overdrive (15) (Fig. 1), and
(ii) reverse dipping displays a sympathetic activation great-
er in magnitude than that seen in other conditions display-
ing abnormalities in the nighttime blood pressure pattern,
such as dipping, non-dipping and reverse dipping state
(16). Taken together, the above-mentioned data support
the concept that the adrenergic nervous system is activat-
ed when blood pressure is increased and that the activa-
tion takes place independently of the clinic or ambulatory
type of blood pressure elevation. They also suggest that
in hypertension, the sympathetic overdrive represents a
mechanism potentially responsible for the altered behavior
of nighttime blood pressure proﬁles seen in some hyper-
Sympathetic activation in congestive heart failure
A chronic impairment in cardiac pump function has been
reported to be characterized by an increase in plasma nore-
pinephrine values (17). This increase depends not only on
a reduced tissue clearance of the adrenergic neurotrans-
mitter but also on a “true” augmentation in the secretion
Fig. 1 - Individual and mean
(±SEM) muscle sympathetic nerve
activity (MSNA) values, expressed
as burst incidence over time (bs/
min) and as burst number cor-
rected for heart rate (bs/100hb), in
normotensive subjects (NT) and in
patients with white-coat (WCHT),
“in” and “out” of ofﬁce (EHT)
and masked (MHT) hypertension;
**p<0.01, between groups. Figure
modiﬁed from (15), by permis-
JN_D_08_00149_GRASSI.indd 191 14-04-2009 15:15:26
Grassi et al: Adrenergic mechanisms in CV and renal disease
of norepinephrine from sympathetic nerve terminals, due
to an augmentation in neural sympathetic outﬂow from the
central nervous system (18).
Evidence has been provided that the adrenergic overdrive (i)
parallels the clinical severity of the heart failure state, as ex-
pressed by the New York Heart Association functional class
(19), (ii) is similar in magnitude in ischemic and nonischemic
heart failure states (20) and (iii) depends on a dysfunction in
the reﬂex mechanisms devoted to blood pressure and adren-
ergic control, such as the arterial baroreceptors (19, 20).
In recent years, information on the neuroadrenergic abnor-
malities documented in heart failure has been considerably
increased with evidence that the neuroadrenergic abnor-
malities characterizing this clinical condition have prog-
nostic relevance, with an increase in systemic as well as
cardiac sympathetic drive being associated with a reduced
survival rate (21, 22). This may explain why sympathetic
deactivation represents a major goal of the therapeutic ap-
proach to this clinical condition (23).
Sympathetic overdrive in obesity and metabolic
An incentive for studying adrenergic function in metabolic dis-
orders and speciﬁcally in obesity comes from the observa-
tion that diminished basal sympathetic activity and reduced
neuroadrenergic responses may cause a positive energy
balance and may therefore contribute to the development of
obesity (24, 25). Although somewhat heterogeneous, the data
obtained have not allowed us to conﬁrm this hypothesis. In
Fig. 2 - Schematic drawing illustrating the possible mecha-
nisms and effects of adrenergic activation in renal failure pa-
tients. GFR = glomerular ﬁltration rate; NO = nitric oxide.
contrast, they have shown that human obesity, particularly in
its visceral form (so-called central obesity), is characterized
by a marked sympathetic activation affecting the whole car-
diovascular system, but particularly the muscle and the renal
circulation (26-28), which participate in insulin metabolism,
as well as blood pressure control, respectively. Recently, the
picture of the adrenergic abnormalities occurring in human
obesity has been made more complex by the ﬁnding that
metabolic syndrome – i.e., the condition in which visceral
obesity, high blood pressure, low high-density lipoprotein
cholesterol, dyslipidemia and insulin resistance are clus-
tered together – displays a marked sympathetic overdrive,
detectable even when high blood pressure is excluded
from the data analysis (25, 29, 30).
What may be the basis for the activation of the sympathetic
nervous system in obesity? Several hypotheses, not mutu-
ally exclusive, have been advanced. It has been thought,
for example, that sleep apnea syndrome, which frequently
characterizes human obesity, might be responsible for a
large portion of the sympathetic activation, given the evi-
dence that chemoreﬂex stimulation brought about by the
hypoxic state characterizing the obese condition triggers
sympathoexcitatory effects (31). However, a recent study
by our group seems to rule out this hypothesis, by showing
that sympathetic activation is detectable in obese subjects
independently of the concomitant presence of sleep apnea
syndrome with overnight polysomnographic evaluation (32).
Another hypothesis claims that the insulin resistance state
(and the consequent hyperinsulinemia) accompanying hu-
man obesity might participate in the phenomenon, taking
into account that (i) insulin triggers central sympathoexcita-
tory effects (33) and (ii) sympathetic activation is greater in
magnitude in central obesity than in peripheral obesity (27),
thereby paralleling the greater level of insulin resistance de-
scribed in the conditions characterized by an excessive ab-
dominal fat depot. Sympathetic nervous system activation
could possibly be driven by at least 2 further mechanisms.
The ﬁrst is represented by leptin (i.e., the protein released
from the adipose tissue and implicated in body weight
homeostasis), given the evidence that hyperleptinemia (i)
is a common ﬁnding in human obesity and (ii) triggers, at
least in experimental animal models, a marked sympathetic
activation (34). A further mechanism could be an abnor-
mality in the baroreﬂex mechanisms which physiologically
restrain sympathetic renal outﬂow. Indeed, evidence has
been provided in favor of this hypothesis, because human
obesity is characterized, even when blood pressure is still
in the normal range, by a clear-cut impairment in baroreﬂex
modulation of the sympathetic neural drive.
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JNEPHROL 2009; 22:190-195
Sympathetic neural activation in renal failure
As schematically depicted in Figure 2, sympathetic activa-
tion represents a hallmark of the chronic renal failure state
and contributes, together with the stimulation of the renin-
angiotensin-aldosterone system, to the clinical progression
of the disease, by producing a number of renal and extra-
renal structural and functional alterations (5). In addition,
renal failure represents, together with heart failure, one of
the pathological states in which a relationship between the
degree of sympathetic activation and the disease progno-
sis have been reported (21, 22, 35).
Direct microneurographic assessment of efferent post-
ganglionic sympathetic nerve trafﬁc has conﬁrmed that
adrenergic overdrive is common in renal failure (36, 37).
However, little information is available on how early in the
clinical course of the disease this neurogenic abnormality
takes place. Preliminary evidence obtained by our group,
however, seems to indicate that in the milder forms of the
disease, characterized by a slight reduction in creatinine
clearance, muscle sympathetic nerve trafﬁc is already el-
evated compared with a group of healthy subjects (38).
Signals arising in the failing kidneys seem to mediate the
adrenergic overdrive in chronic renal failure (37). Other
mechanisms, however, cannot be denied. These include (i)
renal chemoreceptor activation (39, 40), (ii) activation of the
renin-angiotensin-aldosterone system (41), (iii) increased
circulating levels of endogenous inhibitors of the nitric ox-
ide synthase, such as asymmetric dimethylarginine (42-44)
and (iv) the insulin resistance state characterizing a con-
sistent fraction of renal failure patients (25, 45). A further,
intriguing hypothesis afﬁrms that the renal failure–related
adrenergic overdrive reﬂects in some way an impairment of
arterial baroreceptors to modulate the sympathetic neural
drive. This hypothesis, however, has not always received
univocal conﬁrmation. This is in contrast to what has been
reported for baroreﬂex control of vagal activity, which ap-
pears to be already deranged in the initial phases of the
disease, becoming more and more impaired when renal
function further worsens (46). From a pathophysiological
viewpoint, 2 other aspects of the sympathetic activation
of the renal failure state deserve to be mentioned. These
include the evidence that the adrenergic overdrive does not
uniformly affect the entire cardiovascular system, the sym-
pathetic activation described in the skeletal muscle district
being associated with a normal adrenergic outﬂow in the
skin circulation (47). These also include the data showing
that in renal failure the elevated circulating plasma levels
of norepinephrine are related to the concentric type of left
ventricular hypertrophy (48), a ﬁnding that underlines the
concept that sympathetic cardiovascular inﬂuences par-
ticipate in renal failure in the development and progression
of end-organ damage.
The data discussed above suggest that the sympathetic
nervous system represents in renal failure a promising tar-
get the therapeutic intervention. Short daily hemodialysis,
in contrast to the twice-weekly standard hemodialytic pro-
cedure, reduces both sympathetic nerve trafﬁc and blood
pressure values (49). Similarly, drugs interfering with the
renin-angiotensin system may exert, when administered
alone (50) or combined with imidazoline-I1 receptor ago-
nists (51), sustained sympathoinhibitory effects. Correction
of the above-mentioned reﬂex and metabolic abnormalities
may also have a favorable impact on the prevailing sym-
pathetic dysfunction seen in both mild and in more severe
renal failure. The therapeutic sympathoinhibition may re-
sult in a favorable effect on end-organ damage, by slowing
down and possibly reversing the cardiac structural altera-
tions (left ventricular hypertrophy) as well as the vascular
atherosclerotic lesions, particularly at the level of the carot-
id arteries. Therapeutic modulation of adrenergic overdrive,
however, may also have a favorable impact on patient sur-
vival, given the evidence that in renal failure, sympathetic
activation is directly related to cardiovascular mortality (35).
This concept is currently being tested in studies aimed at
determining the impact on survival of therapeutic interven-
tions designed at functionally denervating the human kid-
ney through the use of catheter-based devices (46). The
results for this innovative procedure will be available in the
Financial Support: No ﬁnancial support.
Conﬂict of interest statement: None declared.
Address for correspondence:
Prof. Guido Grassi
Clinica Medica, Ospedale S. Gerardo
Via Pergolesi 33
I-20052 Monza, Milano, Italy
JN_D_08_00149_GRASSI.indd 193 14-04-2009 15:15:29
Grassi et al: Adrenergic mechanisms in CV and renal disease
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Received: October 16, 2008
Accepted: October 21, 2008
© Società Italiana di Nefrologia
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