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Sympathetic activation in cardiovascular and renal disease

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Given the importance of adrenergic neural functioning in cardiovascular control, the hypothesis that an elevation in sympathetic drive represents a key pathophysiological feature of diseases characterized by an impairment 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 objective 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 sympathetic 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 implications, which involve the need to use treatments that oppose rather than enhance sympathetic neural activation.
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190
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 -
Italy
3Auxologico Center Milan - Italy]
Sympathetic activation in cardiovascular and
renal disease
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-
vation.
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
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191
JNEPHROL 2009; 22:190-195
191
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-
tensive states.
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-
sion.
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Grassi et al: Adrenergic mechanisms in CV and renal disease
192
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
syndrome
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.
Therapeutic implications
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
near future.
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
guido.grassi@unimib.it
JN_D_08_00149_GRASSI.indd 193 14-04-2009 15:15:29
194
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Received: October 16, 2008
Accepted: October 21, 2008
© Società Italiana di Nefrologia
JN_D_08_00149_GRASSI.indd 195 14-04-2009 15:15:30
... Convincing evidence has been provided for the role of increased activity of the sympathetic nervous system in the development of cardiovascular diseases [11][12][13]. It has also been shown that salt sensitivity can be attributed to sympathetic overactivity, increased adrenaline release, and enhanced vascular sensitivity to α-adrenoreceptor activation rather than to reduced renal sodium excretion. ...
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Sympathetic nervous system dysregulation and vascular impairment in neuronal tissue beds are hallmarks of prominent cardiorespiratory diseases. However, an accurate and convenient method of assessing SNA and local vascular regulation is lacking, hindering routine clinical and research assessments. To address this, we investigated whether spectral domain optical coherence tomography (OCT), that allows investigation of retina and choroid vascular responsiveness, reflects sympathetic activity in order to develop a quick, easy and non-invasive sympathetic index. Here, we compare choroid and retina vascular perfusion density (VPD) acquired with OCT and heart rate variability (HRV) to microneurography. We recruited 6 healthy males (26 ± 3 years) and 5 healthy females (23 ± 1 year) and instrumented them for respiratory parameters, ECG, blood pressure and muscle sympathetic nerve microneurography. Choroid VPD decreases with the cold pressor test, inhaled hypoxia and breath-hold, and increases with hyperoxia and hyperpnea suggesting that sympathetic activity dominates choroid responses. In contrast, retina VPD was unaffected by the cold pressor test, increased with hypoxia and breath hold and decreases with hyperoxia and hyperpnea, suggesting metabolic vascular regulation dominates the retina. With regards to integrated muscle sympathetic nerve activity, HRV had low predictive power whereas choroid VPD was strongly (inversely) correlated with integrated muscle sympathetic nerve activity (R = −0.76; p < 0.0001). These data suggest that Functional-OCT may provide a novel approach to assess sympathetic activity and intrinsic vascular responsiveness (i.e., autoregulation). Given that sympathetic nervous system activity is the main determinant of autonomic function, sympathetic excitation is associated with severe cardiovascular/cardiorespiratory diseases and autoregulation is critical for brain health, we suggest that the use of our new Functional-OCT technique will be of broad interest to clinicians and researchers.
... The hypothalamic paraventricular nucleus (PVN) is a critical site for central integration of sympathetic outflow to the cardiovascular system [27]. Furthermore, presympathetic PVN neurons have consistently been identified as making a significant contribution to the sympatho-excitation evident in (patho) physiological conditions [3,7,15]. ...
... Although the SON and PVN are two anatomically distinct nuclei, their similar neurochemistry and cellular make up suggests that the control of tonic inhibition could be controlled in a similar manner. Hypertension and pregnancy are two conditions that display significant elevations in sympathetic nerve activity (SNA) resulting, in part from disruption in the neurochemical milleu of the PVN [7,9,13]. In hypertension, this sympatho-excitation results in an increase in blood pressure, whereas in pregnancy the sympathoexcitation contributes to hypervolaemia [9,10,13]. ...
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A characteristic of both hypertension and pregnancy is increased sympathetic nerve activity. The level of sympathetic activation is determined, in part, by a tonic GABAergic inhibition arising from the hypothalamic paraventricular nucleus (PVN). In hypertension, decreases in GABAergic inhibition and increases in glutamatergic excitation within the PVN contribute to this sympatho-excitation. In late-term pregnancy however, the sympatho-excitation appears to be mediated by decreases in GABAergic inhibition only. This study examined whether changes in subunit expression for GABAA receptors in the PVN could provide a molecular basis for the sympatho-excitation characteristic of hypertension and pregnancy. Hypertension and pregnancy were accompanied by significant decrease in the GABAA receptor α5 subunit in the PVN. We suggest that decreases in the α5 subunit of the GABAA receptor may be important in mediating the sympatho-excitation observed in both hypertension and pregnancy.
... As a prolonged sympathetic activation has been associated with severe physiological consequences, including cardiovascular and metabolic diseases (e.g. Grassi et al., 2009), we deem it an important endeavour for future research to consider such objective wellbeing indicators more often. ...
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... The RAS, 109 the SNS, 153 insulin-related endothelin-1 production 154 and OS 28 promote proliferation, migration, senescence, apoptosis, autophagy of vascular smooth muscle cell and vascular remodeling of resistance vessels of the systemic circulation and of renal vessels, as well as peripheral and renal vasoconstriction and peripheral vascular resistance, increase heart rate, stroke volume, renin secretion and tubular sodium reabsorption, and thereby contribute to the development of hypertension and atherosclerosis. 111,149,155,156 Activation of the RAS stimulates accumulation of lowdensity lipoproteins, particularly the oxidatively modified form, in blood vessels which plays an important role in atherosclerotic plaque formation, progression and destabilization. ...
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... This is suggested by the evidence that markers of vascular function are inversely related to various measures of sympathetic discharge (Sverrisdottir et al., 2010; Swierblewska et al., 2010 ), and it is in line with the induction of endothelial dysfunction by sympatho-excitatory maneuvers (Padilla et al., 2010 ). Adrenergic activation is also chronically present in several cardiovascular diseases: this represents a detrimental and maladaptive phenomenon, possibly inducing chronic changes in vascular function and structure, namely vascular remodeling (Grassi et al., 2009). Moreover, chronic adrenergic hyperactivity is involved in the pathogenesis of several cardiovascular risk factors , thus indirectly inducing vascular dysfunction and damage (Lembo et al., 1992; Joyner et al., 2008). ...
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# ACTIVATED INTRARENAL RENIN-ANGIOTENSIN SYSTEM IS CORRELATED WITH HIGH BLOOD PRESSURE IN HUMANS {#article-title-2} to the editor: Dr. Esler ([1][1]) states that Dr. Navar did not provide evidence demonstrating that the activation of the intrarenal renin-angiotensin system (RAS) is the primary
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In this study, we tested the hypothesis that participants higher in dispositional self-compassion would show lower stress-induced reactivity of salivary alpha-amylase (sAA), a marker of sympathetic nervous system activation. Thirty-three healthy participants (18– 34 years old) were exposed to a standardized laboratory stressor on two consecutive days. Self-compassion, self-esteem, and demographic factors were assessed by questionnaire, and sAA was assessed at baseline and at 1, 10, 30, and 60 min following each stressor. Self-compassion was a significant negative predictor of sAA responses on both days. This relationship remained significant when controlling for self-esteem, subjective distress, age, gender, ethnicity, and body mass index. These results suggest that self-compassion may serve as a protective factor against stress-induced physiological changes that have implications for health. Acute psychosocial stress activates a biological fight-or-flight response that includes the activation of the sympathetic nervous system and the release of epinephrine and norepinephrine, which increase heart rate and blood pressure and induce other physiological changes (Frankenhaeuser et al., 1978). These changes increase energy and alertness to help the organism cope more effectively with threats in the environment, but repeated activation of the stress response can contribute to the wear-and-tear of critical organ systems (McEwen, 1998) and increase disease risk (e.
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Background— Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure. Methods and Results— We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Ø, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean±SEM. MSNA was significantly elevated in hemodialysis patients (43±4 bursts/min), RTX-CSA (44±5 bursts/min), RTX-FK (34±3 bursts/min), and RTX-Ø (44±5 bursts/min) as compared with CON (21±3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20±3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44±6 versus 43±5 bursts/min, P=NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney. Conclusions— Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.
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The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.
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Resting plasma concentrations of norepinephrine, dopamine-beta-hydroxylase enzyme activity and peripheral blood lymphocyte beta adrenergic receptor sensitivity to isoproterenol as reflected in cyclic 3′,5′-adenosine monophosphate (cAMP) generation were studied in patients with congestive heart failure due to atherosclerotic heart disease or to congestive cardiomyopathy or hypertensive cardiovascular disease. Systolic time Intervals were also measured in nonhypertensive patients and correlated with the plasma norepinephrine concentration. Control patients were hospital employees without a previous history of heart disease or hypertension, and were matched for age to eliminate the effect of increasing age on the plasma norepinephrine concentration.The results of this study clearly demonstrate that the plasma norepinephrine concentration is directly related to the degree of left ventricular dysfunction in patients with congestive heart failure. When the systolic time intervals were correlated with the plasma norepinephrine levels, a significant prolongation of the preejection period was observed with progressively increasing plasma concentrations of norepinephrine. The reverse was true for the left ventricular ejection time, which demonstrated a significant Inverse relation with the plasma norepinephrine concentration. The ratio of the preejection period to the left ventricular ejection time, which is a reflection of left ventricular function, significantly increased with increasing levels of plasma norepinephrine. In addition, plasma lymphocytes from patients with the greatest degree of left ventricular dysfunction failed to generate normal amounts of cAMP after beta adrenergic receptor stimulation with isoproterenol. It Is suggested that beta adrenergic receptors are desensitized in these patients and that this desensitization contributes to the observed alterations in myocardial contractility.
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Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity. Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.
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Of 691 healthy (untreated) villagers of Tecumseh, Michigan (average age 32.6 years), 99 had a clinical blood pressure exceeding 140/90 mmHg. Thirty-seven per cent of these borderline hypertensives had increased heart rate, cardiac index, forearm blood flow and plasma norepinephrine. These subjects had elevated self-determined home blood pressure (average of 14 measurements). The present hyperkinetic borderlines had elevated blood pressure at 5, 8, 21 and 23 years of age and their parents also had higher blood pressure. The prevalence of high blood pressure in Tecumseh, its long history, elevated blood pressure readings outside the physician's office and family background of hypertension, suggests that the hyperkinetic state is a significant clinical condition. Previous studies on hospital-based populations proved that the hyperkinetic state is caused by an excessive autonomic drive. The association of the hyperkinetic state with elevated norepinephrine in this study suggests that a sympathetic hyperactivity is present in a large proportion of unselected subjects with mild blood pressure elevation.
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Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge), we noted a preferential activation of the cardiac sympathetic outflow; however, in fainting reactions ("vasovagal syncope"), which occur infrequently during the course of central venous catheter placement under local anesthesia, the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients), a differentiated activation of the sympathetic outflow to the heart and kidneys is present, based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade, brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study, we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects, suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.