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Sympathetic activation in cardiovascular and renal disease


Abstract and Figures

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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JNEPHROL 2009; 22: 000-000 –
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
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-
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-
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-
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.
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
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
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. ...
... In addition to hyperinsulinaemia-mediated renal tubular sodium transports, it has also been suggested that the increased glomerular filtration of glucose may enhance the activity of the proximal tubular Na+-glucose cotransporter and may contribute to sodium retention [17]. 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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... Expression of adrenergic receptor genes in the vascular wall of hypertensive ISIAH rats зом почках, поддерживая высокое АД (Grassi et al., 2009; Назарова О.А., Назарова А.В., 2012). В регуляции сосудистого тонуса со стороны САС принимают участие альфа1-, альфа2и бета-адренорецепторы, локализованные в стенке сосудов (Guimaraes, Moura, 2001). ...
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Arterial hypertension is a common disease, which reduces the quality of life and leads to fatal cardiovascular complications. The sympathetic adrenal system is involved in the regulation of blood pressure and in the pathogenesis of arterial hypertension. To date, it is known that stress, together with a hereditary predisposition, is one of the important factors contributing to the development of arterial hypertension in the human population. Using selection for an increase in blood pressure under conditions of mild emotional stress, ISIAH rats that are characterized by a number of morphological and physiological traits typical for patients with essential hypertension were obtained at the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences (Novosibirsk, Russia). The studies point to increased sympathetic adrenal system function in the hypertensive ISIAH line. However, an increase in blood pressure in response to stress stimulation is possible may depend on a genetically determined change in the expression profile of adrenergic receptor genes in the arterial wall. The aim of the work was to study the expression of alpha1A-, alpha1B-, alpha2A-, beta1-, beta2-adrenergic receptor genes in the vascular artery wall of ISIAH rats with stress-sensitive arterial hypertension. Decreased mRNA levels of Adra1A and Adra1B adrenoreceptor genes mediating vasoconstriction in the tail artery in ISIAH rats have been found, which may indicate compensatory changes under conditions of arterial hypertension. In addition, the absence of mRNA expression of the beta1-adrenergic receptor gene in the arterial wall of the studied rat strain was shown, which indicates on predominant role the beta2-adrenergic receptors in this vessel.
... Renal tissue was collected from 15-week-old male and female blood pressure normal (BPN/3J) mice or blood pressure high (BPH/2J, also known as Schlager) mice [3,8]. Our BPH/2J Schlager mice with neurogenic hypertension [9,10] are a highly relevant mouse model since they mimic human disease with increased sympathetic activity [9], elevated heart rate and heightened blood pressure [8,11] driven by neurogenic mechanisms [12]. All dissections were carried out at the Royal Perth Hospital (RPH) animal holding facility in accordance with the guidelines of the RPH Animal Ethics Committee (R537/17-20, approval date 17 August 2017). ...
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Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls. However, there was a need to examine SGLT1 expression in other tissues, such as the kidneys. Whether NE may directly affect SGLT1 protein expression has not yet been investigated, although such a link has been shown for sodium glucose cotransporter 2 (SGLT2). Hence, we aimed to determine (i) whether our murine model of neurogenic hypertension displays elevated renal SGLT1 expression and (ii) whether NE may directly promote elevations of SGLT1 in human proximal tubule (HK2) cells. We did indeed demonstrate that in vivo, in our mouse model of neurogenic hypertension, hyperactivation of the SNS promotes SGLT1 expression in the kidneys. In subsequent in vitro experiments in HK2 cells, we found that NE increased SGLT1 protein expression and translocation as assessed by both specific immunohistochemistry and/or a specific SGLT1 ELISA. Additionally, NE promoted a significant elevation in interleukin-6 (IL-6) levels which resulted in the promotion of SGLT1 expression and proliferation in HK2 cells. Our findings suggest that the SNS upregulates SGLT1 protein expression levels with potential adverse consequences for cardiometabolic control. SGLT1 inhibition may therefore provide a useful therapeutic target in conditions characterized by increased SNS activity, such as chronic kidney disease.
... 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. ...
Based on the conservation of resources theory, we argue that work engagement involves resource investment, and therefore physiologically depletes resources. On this basis, we propose that work engagement accompanies high sympathetic arousal at the within- and the between-person levels, i.e. a negative objective health effect contrary to previous findings of beneficial effects on subjective psychological outcomes. To test our hypotheses, we examined heart rate variability via ambulatory assessment of 118 public office employees across five workdays. We measured daily work engagement at the end of each workday and calculated low frequency normalised and low to high frequency ratio (indicators of sympathetic activation) for work, leisure, and sleeping times of each day. As assumed, multilevel analyses showed a positive relationship between work engagement and sympathetic activation at work, during leisure, and sleeping time at the between-person level. Our hypotheses concerning the within-person associations were not supported. Thus, elevated work engagement over one workweek is associated with higher sympathetic activation, which is discussed to be a health risk.
... 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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Westernized populations are plagued by a plethora of chronic non-infectious degenerative diseases, termed as "civilization diseases", like obesity, diabetes, cardiovascular diseases, cancer, autoimmune diseases, Alzheimer's disease and many more, diseases which are rare or virtually absent in hunter-gatherers and other non-westernized populations. There is a growing awareness that the cause of this amazing discrepancy lies in the profound changes in diet and lifestyle during recent human history. This paper shows that the transition from Paleolithic nutrition to Western diets, along with lack of corresponding genetic adaptations, cause significant distortions of the fine-tuned metabolism that has evolved over millions of years of human evolution in adaptation to Paleolithic diets. With the increasing spread of Western diet and lifestyle worldwide, overweight and civilization diseases are also rapidly increasing in developing countries. It is suggested that the diet-related key changes in the developmental process include an increased production of reactive oxygen species and oxidative stress, development of hyperinsulinemia and insulin resistance, low-grade inflammation and an abnormal activation of the sympathetic nervous system and the renin-angiotensin system, all of which play pivotal roles in the development of diseases of civilization. In addition, diet-related epigenetic changes and fetal programming play an important role. The suggested pathomechanism is also able to explain the well-known but not completely understood close relationship between obesity and the wide range of comorbidities, like type 2 diabetes mellitus, cardiovascular disease, etc., as diseases of the same etiopathology. Changing our lifestyle in accordance with our genetic makeup, including diet and physical activity, may help prevent or limit the development of these diseases.
Hypertension is not only highly prevalent in patients with chronic kidney disease (CKD), it is also one of the most prevalent causes of progressive kidney injury and end‐stage kidney disease. In the context of clinical evaluation of the patient with CKD, four different assessments of blood pressure (BP) are being used: in‐office manual, multiple in‐office automated, home, and ambulatory measurements. Volume overload is the consequence of a too excessive sodium intake and the impaired ability of the kidney to excrete sodium at normal arterial pressures. Renal artery stenosis also leads to diagnostic and therapeutic dilemmas. There are numerous studies in the literature about weight loss and its effects on BP, whether by dietary or pharmacological intervention or by bariatric surgery. Hypertension is not only prevalent in patients with CKD, it is also a key factor to control cardiovascular events in patients with CKD and to prevent progression of CKD itself.
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Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition. Key Words: denervation, heart, hypertension, kidney, SGLT2, sympathetic nervous system
Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to normotensive rats. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the β-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.
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.
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.
Limited information is available on whether and to what extent the different patterns of the nocturnal blood pressure profile reported in hypertension are characterized by differences in sympathetic drive that may relate to, and account for, the different day-night blood pressure changes. In 34 untreated middle-aged essential hypertensive dippers, 17 extreme dippers, 18 nondippers, and 10 reverse dippers, we assessed muscle sympathetic nerve traffic, heart rate, and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and stimulation. Measurements were also performed in 17 age-matched dipper normotensives. All patients displayed reproducible blood pressure patterns at 2 different monitoring sessions. The 4 hypertensive groups did not differ by gender or 24-hour or daytime blood pressure. Muscle sympathetic nerve traffic was significantly higher in nondipper, dipper, and extreme dipper hypertensives than in normotensive controls (58.6+/-1.8, 55.6+/-0.9, and 53.3+/-0.8 versus 43.5+/-1.4 bursts/100 heartbeats, respectively; P<0.01 for all), a further significant increase being detected in reverse dippers (76.8+/-3.1 bursts/100 heartbeats; P<0.05). Compared with normotensives, baroreflex-heart rate control was similarly impaired in all the 4 hypertensive states, whereas baroreflex-sympathetic control was preserved. The day-night blood pressure difference correlated inversely with sympathetic nerve traffic (r=-0.76; P<0.0001) and homeostasis model assessment index (r=-0.32; P<0.005). Thus, the reverse dipping state is characterized by a sympathetic activation greater for magnitude than that seen in the other conditions displaying abnormalities in nighttime blood pressure pattern. The present data suggest that in hypertension, sympathetic activation represents a mechanism potentially responsible for the day-night blood pressure difference.
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.
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.
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.
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.