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Renal Nerves: Roles inHomeostasis
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andPathophysiology
RomanTyshynsky, LucyVulchanova, andJohnOsborn
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Introduction
The kidneys play a central role in the regulation of body uid
homeostasis. Processes throughout the nephron contribute to
this regulation, including the glomerular ltration of blood,
and the exchange of solutes and water between tubules and
peritubular capillaries. These processes result in the excretion of excess water, solutes, and waste in the urine, and are
regulated by intrinsic renal mechanisms and hormonal controllers such as the renin-angiotensin-aldosterone system.
Renal function is also under the control of sensory and sympathetic innervation of the kidney [1], which will be the
focus of this chapter.
Increased renal sympathetic (efferent) nerve activity
results in sodium retention via a decrease in glomerular ltration rate and an increase in tubular sodium reabsorption.
Furthermore, renal sympathetic nerves stimulate the release
of renin, initiating the renin-angiotensin-aldosterone system,
leading to sodium retention and constriction of the peripheral vasculature. These synergistic actions of renal sympathetic nerves are consistent with the hypothesis that
chronically increased renal nerve activity leads to hypertension. This hypothesis and successful renal denervation
(RDN) procedures on animal models of hypertension form
the theoretical framework that supports RDN as a treatment
for hypertension in humans [1, 2].
Catheter-based renal nerve ablation (CBRNA) for the
treatment of hypertension is producing promising results in
clinical trials [3, 4]. This technique indiscriminately ablates
sensory and sympathetic nerves traveling from and to the
kidney, respectively. Moreover, unpredicted outcomes of
CBRNA clinical trials, including improved glucose metabolism, reduced incidences of cardiac arrhythmias, and reduced
R. Tyshynsky · L. Vulchanova · J. Osborn (*)
University of Minnesota, Minneapolis, MN, USA
e-mail: tyshy003@umn.edu; vulch001@umn.edu;
osbor003@umn.edu
sympathetic activity to skeletal muscle have sparked renewed
interest in understanding the role of renal nerves in disease
states [5]. These ndings suggest that renal sensory (afferent) nerves, which relay information to the central nervous
system to modulate sympathetic activity to several organs,
may contribute to the additional therapeutic effects of
CBRNA.
Here we present the current knowledge of the anatomy
and physiology of renal sympathetic and sensory nerves in
the regulation of renal function in physiological and pathophysiological states.
Renal Nerves inHomeostasis
Sympathetic (Eerent) Renal Nerves
As illustrated in Fig.1.1 (left side), postganglionic sympathetic (efferent) renal nerves originate from paravertebral
and prevertebral ganglia (i.e. superior mesenteric, celiac, and
aorticorenal sympathetic ganglia). These nerves form neuroeffector junctions with their renal targets, which include
the juxtaglomerular cells of the afferent arterioles to stimulate renin release, the renal tubules to enhance sodium reabsorption, and the afferent arteriole to regulate renal vascular
resistance and glomerular ltration rate [6–9]. The current
understanding of the sympathetic innervation of the kidney
and its functions are discussed in our recent review [1]. Renal
sympathetic bers release norepinephrine as the primary
neurotransmitter and co-transmitters such as adenosine triphosphate (ATP), vasoactive intestinal peptide (VIP), and
neuropeptide Y (NPY), among others [10]. Although the
details regarding the role of adrenergic (i.e. norepinephrine)
versus purinergic (i.e. ATP) and peptidergic (i.e. VIP, NPY)
signaling are still under investigation, the primary summatory results of increased efferent activity to the kidneys are:
(1) vasoconstriction of the afferent arterioles resulting in
increased renal vascular resistance and decreased glomerular
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_1
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Fig. 1.1 Anatomy of renal nerve pathways and roles in homeostasis.
Sympathetic (efferent) renal nerves receive central input from the PVN
and RVLM, whose neurons synapse onto neurons in the intermediolateral (IML) column of the spinal cord. These preganglionic neurons
project to postganglionic neurons in the sympathetic ganglia, which
project to their neuroeffector sites in the kidney. Sympathetic renal
nerves maintain hemodynamics by causing renin release by juxtaglomerular cells, constricting peripheral vasculature to increase vascular
ltration rate, (2) activation of the renin angiotensin system
by stimulation of renin release, and (3) increased tubular
sodium reabsorption [1].
The activity of renal sympathetic postganglionic neurons
is driven by preganglionic neurons whose cell bodies are
located in the intermediolateral (IML) cell column of the spinal cord (Fig.1.2). The rostral ventrolateral medulla (RVLM)
of the brainstem and the paraventricular nucleus (PVN) of
the hypothalamus play a large role in the regulation of renal
sympathetic nerve activity (RSNA), as they send excitatory
projections to renal preganglionic neurons and are under the
inuence of a number of sensory inputs to the brain related
to cardiovascular and body uid homeostasis [11–16]. For
example, reductions in central blood volume increase RSNA
in response to decreased activity of cardiopulmonary baroreceptor input to the brainstem [17], resulting in sympathetically mediated afferent arteriolar constriction (i.e., decreased
glomerular ltration), activation of the renin angiotensin sys-
resistance, and increasing sodium reabsorption by the tubules. Bilateral
dorsal root ganglia neurons project both to the kidney and to neurons of
dorsal horn of the spinal cord. These neurons then project centrally to
the nucleus of the solitary tract (NTS), as well as the RVLM and
PVN.While the function of sensory renal nerves in homeostasis are not
fully elucidated, they are known to be mechanosensitive and chemosensitive, and initiate reexes, both sympathoinhibitory and sympathoexcitatory. (Adapted from Osborn, Tyshynsky, and Vulchanova [1])
tem, and increased tubular sodium reabsorption, all of which
act to restore blood volume. This renal sympathoexcitatory
pathway is also modulated by several circulating hormones
such as angiotensin II and aldosterone [18–20]. It is believed
that, under normal physiological conditions, the integration
of neural and hormonal inputs within these hypothalamic
and brainstem circuits regulate RSNA to maintain body uid
and cardiovascular homeostasis [21].
Sensory (Aerent) Renal Nerves
The kidney is also richly innervated by sensory nerves that
respond to changes in the internal renal environment
(Fig.1.1, right side). The greatest emphasis has been placed
on the sensory innervation of the pelvis because of the high
density of sensory bers in the smooth muscle, epithelial,
and subepithelial layers of the pelvis compared to other renal
ab
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Fig. 1.2 Role of Brain-Kidney Axis and Kidney-Brain Axis in pathology. Overactivity of the Brain-Kidney Axis (a) can initiate hypertension
and renal inammation via increases in renin release, sodium reabsorption, vascular resistance, and trafcking or activation of macrophages,
T-cells, and the release of cytokines in the kidney. Consequently, renal
inammation is a cause of increased sensory renal nerve activity, acti-
structures [21–25]. However, anterograde tracing experiments have demonstrated that sensory bers are associated
with all branches of the intrarenal arteries as well as a sparse
association with intrarenal veins [22]. More recent studies
have emphasized the potential importance of previously
overlooked innervation of cortical structures in the kidney,
including the afferent and efferent arterioles [26], as well as
glomeruli [27]. The function of these cortical sensory bers
is largely still a question. The primary modalities of sensory
renal nerves are mechanosensation to sense increased stretch
in the pelvic wall and other structures, and chemosensation
to respond to extreme ischemia and/or sensing changes in
body uid composition (e.g. sodium, potassium osmolarity,
pH) [21, 26, 28, 29].
The role of renal sensory nerves under normal physiological conditions is still unclear. Most of what is known is based
on physiological investigations of pelvic sensory renal nerves
in anesthetized animals and has led to the concept of the
“renorenal reex” [30]. This hypothesis states that activation
of pelvic afferent nerves reexively decreases RSNA resulting in natriuresis and diuresis. It is hypothesized that this
reex is important in the homeostatic regulation of arterial
vating the Kidney-Brain Axis (b). Because the Kidney-Brain Axis projects to central areas that regulate sympathetic activity to many organs,
overactivity of the Kidney-Brain Axis is one cause of hypertension, and
is hypothesized to lead to other conditions, including cardiac arrhythmias, diabetes. (Adapted from Osborn, Tyshynsky, and Vulchanova [1])
pressure in response to signals within the kidney (i.e.,
increased pelvic pressure) that signal volume expansion.
However, it is important to note that studies investigating this
sympathoinhibitory renorenal reex have largely been done
on anesthetized animals.
In contrast, a recent study demonstrated that activation of
renal sensory nerves in the unanesthetized decerebrate rat
results in a sympathoexcitatory, rather than sympathoinhibitory, response [31]. This is consistent with the reports that
intrarenal administration of a known activator of sensory
nerves, such as bradykinin, increases arterial pressure and
heart rate in conscious rats [32, 33]. This renal sympathoexcitatory reex likely results in the activation of sensory pathways that converge at the RVLM of the brainstem and the
PVN of the hypothalamus, both of which are important for
the regulation of sympathetic activity to the kidney as well as
other organs [3, 34–37].
It is likely that specic subsets of renal sensory nerves,
based on location and sensorymodality, elicit different
sympathetic responses where some are sympathoexcitatory
and others are sympathoinhibitory and these responses are
likely key to the maintenance of homeostasis. This is an
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R. Tyshynsky et al.
active area of scientic investigation. Furthermore, it has
been hypothesized that pathological states may inuence
the predominance of sympathoinhibitory or sympathoexcitatory response [30].
Renal Nerves inPathophysiology
Sympathetic Renal Nerves: TheBrain-Kidney
Axis inPathological States
Classical View
The discovery that increased RSNA results in an elevation of
arterial pressure via increased renin release, sodium reabsorption, and vascular resistance led to the idea that CBRNA
could be performed as an effective therapy for the treatment
of hypertension, targeting this “Brain-Kidney Axis” as a
source of hypertension (Fig. 1.2a). This concept was bolstered by numerous preclinical studies in which surgical
renal denervation attenuated the development of several
models of hypertension [38–41]. However, the technical
challenge of recording RSNA in unanesthetized animals and
humans has made it difcult to provide direct evidence of the
activation of the “Brain-Kidney Axis” in hypertension,
although a handful of animal studies have successfully
recorded RSNA during the development of experimental
hypertension [42]. RSNA has been shown to increase in
obesity- induced hypertension in rabbits [43], but it remains
either unchanged or decreased in angiotensin-induced hypertension (as well as the angiotensin-salt model [44–46]. In
contrast, indirect measurements of RSNA such as renal norepinephrine spillover, have been shown to be elevated in
humans with essential hypertension [47]. Thus, elevated
RSNA and the resulting increases in renin release, sodium
reabsorption, and renal vascular resistance, all of which contribute to increased arterial pressure, are classically thought
to cause hypertension.
Renal Nerves andInammation
In addition to the classical view that activation of the BrainKidney Axis causes hypertension, there may also be a relationship between the activity of renal nerves and renal
inammation (Fig.1.2a). This hypothesis was supported by
early experiments in which total renal denervation (efferent
+ afferent; TRDN) protected kidneys from infection following the injection of colon bacilli in dogs and decreased
proteinuria in four out of ve patients with nephritis who
underwent surgical TRDN [48, 49]. More recent studies in
preclinical models further support the hypothesis that the
Brain-Kidney Axis is involved in renal inammation and
brosis. They have demonstrated effects of TRDN such as
amelioration of glomerulonephritis [50], prevention of
interstitial brosis and inammation following ureteral
obstruction [51], and reduction in T-cell accumulation and
renal brosis in the AngII-induced mouse model of hypertension [52].
Studies from our laboratory suggest that renal nerves
mediate the trafcking and/or activation of macrophages in
the kidney in the DOCA-salt rat model of hypertension.
TRDN also prevents the increase of pro-inammatory cytokines (IL-2, IL-6) and chemokines (GRO/KC, MCP-1) in
this model [39]. However, TRDN did not reverse established
renal inammation in DOCA-salt hypertensive rats. Although
these experiments employed TRDN to ablate both sympathetic and sensory renal nerves, these effects are largely
believed to be due to the ablation of the Brain-Kidney Axis.
Sensory Renal Nerves: TheKidney-Brain Axis
inPathological States
Just as renal nerves can cause renal inammation, renal
inammation (regardless of its cause), can, in turn, activate
the Kidney-Brain Axis, resulting in a chronic activation of
the sympathetic nervous system and its resulting pathologies
(Fig.1.2b). Here we summarize how this may contribute to
hypertension as well as other sympathetically driven disease
states.
Hypertension
It is well-established that cytokines released from immune
cells inltrating the kidney as a result of the Brain-Kidney
Axis of hypertension can increase the activity of sensory
bers in the kidney [53–55]. Thus, increased RSNA that can
cause hypertension and renal inammation can also lead to
an increase in sensory renal nerve activity, potentially further
exacerbating the disease state. Renal denervation techniques
are being used to investigate these interactions. While
CBRNA nonselectively ablates both sensory and sympathetic renal nerves, investigators have employed techniques
to specically ablate sensory renal nerves to study the contribution of the Kidney-Brain Axis in preclinical models of
hypertension.
Dorsal rhizotomy is one such technique that has been
used to target sensory renal nerves and spare sympathetic
renal nerves [56], resulting in the attenuation of hypertension
in the phenol renal injury model [57, 58], the Goldblatt
model of renal artery stenosis [59, 60], and the cyclosporine
A-induced model of hypertension [61]. While this technique
spares sympathetic renal nerves where CBRNA and TRDN
do not, it is not specic to sensory nerves from the kidney
alone, ablating all sensory input from all organs at the targeted spinal levels.
To target sensory nerves innervating the kidney specically, our laboratory has developed a more selective method
for the targeted ablation of renal sensory nerves using periax-
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onal capsaicin treatment (Afferent Renal Denervation;
ARDN) [33]. We have employed this technique, in combination with radio telemetric measurement of arterial pressure
in freely moving animals that are subjected to a renal inammatory model of hypertension, the DOCA-salt model. Our
results show that the effect of TRDN on DOCA-salt hypertension is mediated by the ablation of sensory renal nerves
rather than the sympathetic renal nerves, since TRDN and
ARDN attenuate hypertension by the same magnitude [39].
This same result has been shown in the DOCA-salt model in
mouse [62], and the 2K-1C model in rat and mouse [63–65].
Consistent with the hypothesis that sensory renal nerve activity drives hypertension in these models, Rossi and colleagues
have directly measured elevated RSNA in the non-clipped
kidney of unanesthetized 2K-1C rats and this was normalized by the TRDN of the clipped kidney [66]. These results
indicate that sensory renal nerves elicit sympathoexcitatory
responses in the 2K-1C model, suggesting that pathological
conditions may cause a sympathoexcitatory state to predominate in sensory renal nerves.
However, some preclinical models that are ameliorated by
TRDN are unaffected by ARDN, such as the Dahl saltsensitive rat [41]. This difference in the efcacy of ARDN in
different models of hypertension suggests that some causes
of hypertension are driven by sympathetic renal nerves,
while others are driven by sensory renal nerves. Discerning
which axis predominates in animal models and human
patients is needed to develop even more targeted renal nervebased therapies in the future.
Other Clinical Conditions
In addition to hypertension, it is likely that the activation of
the Kidney-Brain Axis and renal inammation may contribute to other clinical conditions that involve the chronic activation of the sympathetic nervous system, and CBRNA may
be used to effectively treat these conditions. For example,
some patients undergoing CBRNA for hypertension in clinical trials saw improvements in glucose metabolism, and
reduced incidences of cardiac arrhythmia and apnea [5].
Furthermore, CBRNA has been proposed as an indication for
patients with chronic and end-stage renal disease because
such diseases cause an increase in muscle sympathetic nerve
activity [3, 35–37]. These effects support the hypothesis that
the Kidney-Brain Axis may be responsible for increases in
sympathetic nerve activity that can lead to other conditions,
including cardiac arrhythmias and diabetes. Further investigations into the mechanisms and physiological effects of
sensory renal nerve activation are necessary to better understand how the Kidney-Brain Axis contributes to hypertension and other conditions, and to inform the improvement of
renal denervation procedures for the treatment of these
conditions.
Given the importance of the Brain-Kidney Axis in the
maintenance of hemodynamics, and the preclinical results
suggesting that some models of hypertension are driven by
Kidney-Brain Axis hyperactivity, it may be benecial to
selectively ablate sensory renal nerves to treat some patients’
conditions. A recent study investigating the effects of
CBRNA in sheep indicated that although the procedure was
successful in lowering arterial pressure in a chronic kidney
disease model in sheep, the sheep that received TRDN had a
compromised ability to respond to hemorrhagic and septic
shock with compensatory hemodynamic processes, likely
due to the loss of the Brain-Kidney Axis [67]. These regulatory processes may be preserved with advancements in
CBRNA techniques to selectively target sensory renal nerves
under conditions of increased activity of the Kidney-Brain
Axis. Unfortunately, there are currently no diagnostic tests or
biomarkers available to identify if a patient’s hypertension is
driven primarily by afferent renal nerves. This is an active
area of investigation.
The Emergence ofCatheter-Based Renal
Nerve Ablation fortheTreatment
ofHypertension andOther Diseases
CBRNA as a treatment for hypertension is centered around
the concept that renal nerve overactivity can cause hypertension, a concept rst established in 1945 by chronic renal
nerve stimulation in dogs [68]. Consequently, clinical trials
investigating the efcacy of CBRNA for the treatment of
hypertension in patients are currently underway, as
reviewed extensively [3, 4]. These procedures typically
involve the advancement of a catheter via the patient’s femoral artery into their renal arteries and employ ablation
techniques targeted to and near the adventitial layer of the
renal artery to ablate renal nerves (Fig.1.3). A variety of
ablation techniques have been introduced for CBRNA procedures, producing similar reductions in arterial pressure 6
months after the outpatient procedure. These include the
the ReCor ParadiseTM catheter (ultrasound), Medtronic
SpyralTM ablation catheter (radiofrequency), and the
Ablative Solutions PeregrineTM catheter (alcohol) [3, 69].
Some of the major advantages of CBRNA over medication
for the treatment of hypertension are its long-lasting
decrease in arterial pressure, and the avoidance of issues
related to drug resistance and patient adherence to
medication.
Clinical trial results suggest that, although ablation of the
Brain-Kidney Axis mediates some of the benecial effects of
CBRNA, ablation of the Kidney-Brain Axis also contributes
to clinical benets of CBRNA [5]. Further investigations into
the roles of renal nerves in the maintenance of homeostasis
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Fig. 1.3 Catheter-based renal nerve ablation. Although different
devices employ different techniques to ablate the renal nerves, the general concept behind each technique remains the same. A catheter is
advanced to the renal artery, and ablative energies (radiofrequency,
ultrasound) or chemical (alcohol) are delivered radially to the periadventitial space. These techniques produce long-lasting effects [3, 5],
ablating both sympathetic and sensory nerves.
and in pathological conditions will help to better inform the
continuing development and renement of renal denervation
techniques.
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Animal andHuman Experience
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inQuantifying theEffects ofRenal
Denervation onSympathetic Nervous
System Activity
DagmaraHering, RichardR.Heuser, andMurrayEsler
2
Introduction
Various experimental models of hypertension and human
studies found that disruption of renal sympathetic nerves has
considerable pathophysiologic consequences resulting in
blood pressure (BP) reduction. However, the BP response to
arterial renal denervation (RDN) in human hypertension is
variable. Insufcient procedural effectiveness resulting in
incomplete nerve disruption has been suggested to explain
treatment-related variation or non-response to RDN.Among
several methods for studying the sympathetic nervous system (i.e. the measurement of the catecholamines in plasma
and/or their metabolites in urine, arterial baroreceptors sensitivity, spectral analysis of heart rate variability, imaging
methods with the use of radioisotopes), regional organspecic norepinephrine (NE) spillover and microneurography are considered the two gold-standard techniques for
quantifying human sympathetic nervous system activity and
have been used to determine the extent of nerve ablation following RDN [1–4].
In preclinical models, the extent of renal nerve ablation
has been widely tested with the assessment of renal cortical
NE tissue content, renal cortical axon density, and immunohistochemical staining using antibodies against makers for
renal efferent sympathetic nerves (tyrosine hydroxylase
[TH], neuropeptide Y [NPY]), and renal afferent sensory
D. Hering (*)
College of Health Solutions, Arizona State University,
Phoenix, AZ, USA
Department of Hypertension and Diabetology, Medical University
of Gdansk, Gdańsk, Poland
e-mail: hering@gumed.edu.pl
R. R. Heuser
College of Health Solutions, Arizona State University,
Phoenix, AZ, USA
University of Arizona, College of Medicine, Phoenix, AZ, USA
M. Esler
Baker IDI Heart and Diabetes Institute, Melbourne, Australia
nerves (calcitonin gene-related peptide [CGRP] and substance P [SP]).
It is worth considering ndings from animal studies showing that the measurement of renal tissue NE content cannot
be used to immediately verify the completeness of acute
RDN at the time when performed, as it generally requires
2–3 days to occur [5]. It has been shown that renal vasoconstrictor response to renal sympathetic nerve stimulation and
basal urinary sodium excretion returns toward normal values
14–24 days after RDN when renal tissue NE content is still
<30% of the control value [6]. This data indicates that the
assessment of completeness of nerve damage achieved with
renal nerve ablation is complex and needs comprehensive
investigation when assessing the efcacy of the procedure
and potential reinnervation.
Noradrenaline Spillover
A breakthrough in research studies on the sympathetic nervous system was the development of the radiotracer technique, based on the measurement of the rate of spillover of
NE to plasma, in the mid-1980s by the author Professor
Murray Esler [7]. This method consists of intravenous
administration (usually into the ulnar vein) in a constant and
continuous ow of a small amount of isotope-labeled NE
(Fig. 2.1). The simultaneous collection of blood from the
venous and arterial vessels allows to distinguish the uptake
of the labeled neurotransmitter and precisely determine the
measurement of NE released from sympathetic nerves to
plasma (total body NE spillover). Regional evaluation of
blood drawn from the coronary sinus or the renal veins with
arterial sampling accurately measures the release of NE from
organ-specic cardiac or renal sympathetic nerves. This
technique provided relevance to numerous previous studies
on the importance of the sympathetic nervous system in the
pathogenesis of human essential hypertension. While body
NE release was approximately 20–25% higher compared to
controls, there was a preferential increase in renal and car-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_2
11
12
https://t.me/medicina_free
Fig. 2.1 Radioisotope
noradrenaline spillover
dilution method
D. Hering et al.
diac neurotransmitter release from sympathetic nerves in
human hypertension, indicating that the kidney and the heart
are two major organs implicated in the development of
human hypertension [8].
Microneurography
Microneurography allows direct recording of postganglionic efferent sympathetic nerve activity to the peroneal
nerve from multiple bers, more precisely from a single
nerve ber (Fig.2.2), innervating either skeletal muscle
vessels [muscle sympathetic nerve activity (MSNA)] or
skin (skin sympathetic nerve activity [SSNA]). Resistance
vessels in the skeletal muscles are major determinants of
ow and vascular resistance. This technique is performed
using two microelectrodes (tip 1–5μm in diameter). One
electrode records the potentials from the sympathetic
bers of the peroneal nerve, and the second electrode is
located 2–3 cm away and serves as the reference electrode. Sympathetic nerve trafc recorded with MSNA is
synchronized with the heart rate (HR) compared to SSNA
impulses whose activity is independent of the HR and is
sensitive to external stimuli (e.g. noise, temperature,
hyperhidrosis). Along with nerve recording is crucial to
record beat-to-beat HR, respiratory rate, and BP to ensure
a comprehensive and accurate assessment of sympathetic
nervous system activity (Fig. 2.2). The advantage of
microneurography is (1) precise assessment of resting
MSNA activity, (2) comparison of sympathetic activity
between selected groups (e.g. healthy controls, patients),
(3) the ability to track changes in the regulation of the
circulatory system during the same registration in response
to various stimuli (e.g. arithmetic test, isometric test, cold
pressor test); and (4) determining the mechanisms inuencing the tonic stimulation of the sympathetic system
(arterial chemoreceptors, arterial baroreceptors, cardiopulmonary mechanoreceptors).
2 Animal andHuman Experience inQuantifying theEects ofRenal Denervation onSympathetic Nervous System Activity
https://t.me/medicina_free
Fig. 2.2 Integrated resting recordings of beat-to-beat heart rate, raw signal for single-unit muscle sympathetic nerve activity (MSNA), multi-unit
MSNA, respiration, and blood pressure of a 42-year-old female with resistant hypertension
13
Is Elevated Heart Rate aBiomarker
ofSympathetic Activation inEssential
Hypertension?
Elevated HR has been suggested as a simple and easy-tomeasure marker indicator of sympathetic nervous system
activation, however, the direct association is complex and
indicates that HR is under partial control of the sympathetic
nervous system [9].
Previous microneurography studies found that MSNA
and HR exerts an interactive effect on BP levels [10]. In nor-
motensive subjects (only males not females) with faster HR,
higher levels of MSNA have been linked to higher systolic
BP and pulse pressure whereas no similar relationship was
found in subjects with lower HR [10]. An association
between resting HR and MSNA in essential hypertension is
complex and not completely understood. It has been documented that HR is not a reliable indicator of overall sympathetic activity as no association has been found between
supine resting ofce HR and MSNA in essential hypertension [11]. Ambulatory HR was found to be a superior risk
marker to a clinic or HR derived from an electrocardiogram
[12]. When 24-h ambulatory BP measurements were performed, a direct relationship between MSNA and ambulatory daytime, and nighttime HR was observed in a large
sample of patients with untreated essential hypertension that
was independent of age, BMI, and gender [13].
Further additional and more specic robust support
comes from the study that applied the isotope dilution
methodology to measure whole body NE spillover, renal
NE spillover and cardiac NE spillover to validate an elevated HR as a sympathetic nervous system biomarker [9].
This study performed in unmedicated patients with essential hypertension and healthy controls shed new light into
the sympathetic nervous system activation underlying the
hypertension pathophysiology. It should be emphasized
that sympathetic activation evident in individual patients
with essential hypertension is differentiated, not necessarily involving simultaneously all sympathetic outows. An
elevated HR in hypertension was directly associated with
cardiac NE spillover only, but not with renal NE spillover
or adrenaline secretion. In this study, 67% of the variance
in HR was attributable to differences in cardiac sympathetic activity. While essential hypertension is characterized by signicantly increased mean cardiac, renal and
total body NE spillover rates, there was no internal correlation between cardiac NE spillover, renal NE spillover and
adrenaline secretion among hypertensive patients. These
ndings clearly indicate that an elevated HR is a valid
marker of cardiac sympathetic activation only. Regional
differentiation of sympathetic activation in human essential
hypertension indicates that no simple a reliable marker test
can ever represent each and every sympathetic outow in
hypertension [9].
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