Neural Control of Blood Pressure : Focusing on Capsaicin-Sensitive Sensory Nerves

Cardiovascular & Haematological Disorders-Drug Targets, 2007, 7, 37-46
37
Neural Control of Blood Pressure: Focusing on Capsaicin-Sensitive

Sensory Nerves
Youping Wang and Donna H. Wang*
Department of Medicine, Neuroscience Program, and Cell and Molecular Program, Michigan State University, East
Lansing, Michigan, USA
Abstract: Hypertension is a major risk factor leading to devastating cardiovascular events such as myocardial infarction,
stroke, heart failure, and renal failure. Despite intensive research in this area, mechanisms underlying essential hyperten-
sion remain to be defined. Accumulating evidence indicates that neural components including both sympathetic and sen-
sory nerves innervating the cardiovascular and renal tissues play a key role in regulating water and sodium homeostasis
and blood pressure, and that abnormalities in these nervous systems contribute to increased salt sensitivity and develop-
ment of hypertension. In contrast to relatively well-defined sympathetic nervous system, the role of sensory nerves in the
control of cardiovascular homeostasis is largely unknown. Data from our laboratory show that degeneration of capsaicin-
sensitive sensory nerves renders a rat salt sensitive in terms of blood pressure regulation. Evidence is also available indi-
cating that sensory nerves, in interacting with other neurohormonal systems including the sympathetic nervous system, the
renin-angiotensin aldosterone system, the endothelin system, and superoxide, regulate cardiovascular and renal function in
such that they play a counter-balancing role in preventing salt-induced increases in blood pressure under pathophysiologi-
cal conditions. Altered activity of the sensory nervous system, a condition existed in both genetic and experimental mod-
els of hypertension, contributes to the development of hypertension. This article focuses on reviewing the current knowl-
edge regarding the possible role of sensory nerves in regulating blood pressure homeostasis as well as the function and
regulation of novel molecules expressed in sensory nerves.
Key Words: Capsaicin, vanilloid receptor, sympathetic nerve, angiotensin II, endothelin, oxidative stress, sodium, blood pres-
sure.
INTRODUCTION
nerves in the control of cardiovascular homeostasis is largely
unknown. Immunocytochemical studies have identified that

Hypertension is one of the most important risk factors for
primary sensory nerve fibers distribute throughout the car-
the development of cardiovascular disease [1], including
diovascular system especially in the resistance arteries (Fig.
coronary artery disease, stroke, left ventricular hypertrophy,
1) [5], suggesting that these nerves may be involved in the
heart failure, and renal insufficiency and end-stage kidney
regulation of cardiovascular homeostasis.
disease. Despite decades of intensive research into the
mechanisms responsible for hypertension, there is still no
consensus regarding the underlying defects or even the se-
quence of hemodynamic events leading to hypertension. In-
creased dietary sodium has long been implicated in the
pathogenesis of hypertension [2]. It is well established that
subjects taking very high dietary sodium have a much
greater incidence of hypertension than those consuming a
low sodium diet [3]. Although animals models of salt-
dependent hypertension have been developed, including ge-
netic, pharmacological, and surgically induced models [4],
the mechanistic link between dietary salt and hypertension
remains poorly understood.

Accumulating evidence indicates that neural components
especially sympathetic nerves innervating the cardiovascular
and renal tissues play a key role in regulating water and so-
dium homeostasis and blood pressure, and that abnormalities
in this nervous system contribute to increased salt sensitivity
and development of hypertension. In contrast to relatively
well-defined sympathetic nervous system, the role of sensory
Fig. (1). Visualization by immunohistochemistry of calcitonin
*Address correspondence to this author at the Department of Medicine, B316
Clinical Center, Michigan State University, East Lansing, MI 48824, USA;
gene-related peptide-like immunoreactivity in the mesenteric artery
Tel: 517-432-0797; Fax: 517-432-1326; E-mail: donna.wang@ht.msu.edu
of a normotensive Wistar rat. Scale bar, 100 M.

1871-529X/07 $50.00+.00
© 2007 Bentham Science Publishers Ltd.

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38 Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1
Wang and Wang

Capsaicin, isolated from hot pepper by Thresh in 1846
[6], leads to excitation of a subpopulation of primary sensory
neurons with somata in dorsal root ganglion (DRG) or tri-
geminal ganglion [7]. The primary sensory neurons excited
by capsaicin include unmyelinated C- and myelinated A -
fibers, which have been described as capsaicin-sensitive sen-
sory neurons given that sensitivity to capsaicin is a common
trait shared by these neurons. Once excited, electrical signals
are generated in these nerves and sent to the central nervous
system. Simultaneously, independent of conducted electrical
impulses, the efferent function of these nerves would allow
the release of vasoactive sensory neuropeptides including
calcitonin gene-related peptide (CGRP) and substance P
from their peripheral nerve endings [7] leading to potent
vasodilation in many vascular beds [8].

The effects of capsaicin are mediated by binding and
activating the transient receptor potential vanilloid type 1
(TRPV1) channel or the vanilloid receptor 1 (VR1), which
belongs to the transient receptor potential (TRP) superfamily
of ion channels [9]. This receptor, primarily expressed in
capsaicin-sensitive sensory neuron and nerve fibers, contains
Fig. (2). Visualization by immunohistochemistry of calcitonin
six transmembrane domains with a re-entrant pore separating
gene-related peptide-like immunoreactivity in the mesenteric artery
the last two domains [9, 10]. It has been suggested that the
of an adult rat neonatally treated with capsaicin (50 mg/kg, sc).
TRPV1 receptor functions as a molecular integrator of pain-
Note that CGRP-positive sensory nerve fibers in the mesenteric
ful chemical and physical stimuli including capsaicin, nox-
artery of this capsaicin-treated rat are remarkably less than in that of
ious heat, and low pH [11]. The fact that activation of the
the control rat shown in Fig. (1).
TRPV1 expressed in sensory neurons leads to release of a
number of potent cardiovascular modulators from nerve end-
CAPSAICIN-SENSITIVE SENSORY NERVES AND
ings indicates that this receptor may play a key role in regu-
SALT-SENSITIVE HYPERTENSION
lation of cardiovascular homeostasis.

Accumulating evidence suggests that capsaicin-sensitive

In 1977, it was reported that an appropriate dose of cap-
sensory nerves and their neurotransmitters are intimately
saicin given to new-born rats sacrificed the majority of
involved in the pathogenesis of hypertension. The effects of
small- to medium-sized DGR neurons [12]. The finding was
these nerves and their neurotransmitters are either direct or
further confirmed by Nagi et al. [13] showing that treatment
mediated by interacting with the sympathetic nervous system
of neonatal rats with capsaicin leads to a permanent destruc-
and vasoactive agents derived from the vasculature and the
tion of up to 90% of peripheral unmyelinated afferent fibers,
kidney. We reported in 1998 that neonatal treatment with
an event possibly linked with deprivation of sensory nerves
capsaicin resulted in an elevation of blood pressure in rats
with nerve growth factor [14]. Since then, neonatal capsaicin
fed a high salt diet but not in rats fed a normal salt diet (Fig.
treatment has been used for identifying the role of capsaicin-
3) [15]. Increased blood pressure in sensory denervated rats
sensitive sensory nerves in pathphysiological regulatory
fed a high salt diet was accompanied by a decease in water
processes. Based on this model, we discovered for the first
and sodium excretion, suggesting the impairment in renal
time that neonatal degeneration of sensory nerves induced by
function in the face of salt challenge in this model. These
capsaicin treatment (Fig. 2) renders a rat to respond to a salt
results are supported by reports from Kopp et al. [16] who
load with a significant and sustained rise in blood pressure
have shown that disruption of afferent renal nerves with sur-
(Fig. 3) [15]. This model provides a novel experimental
gical intervention impairs urinary sodium excretion and in-
paradigm for exploring the mechanisms linked with in-
creases blood pressure in rats fed a high salt diet. These re-
creased salt sensitivity of arterial pressure and sensory nerve
sults are also consistent with the early reports by Burg et al.
function.
[17], showing that selective depletion of spinal substance P
and CGRP in afferent renal nerves with intrathecal admini-

This review focuses on reviewing the current knowledge
stration of capsaicin enhanced the development of one-
regarding the possible role of sensory nerves in regulating
kidney renal wrap hypertension. These findings provide the
blood pressure homeostasis as well as the interaction be-
evidence supporting that afferent renal nerves are important
tween sensory nerves and neuro-hormonal systems control-
in preventing salt-induced increases in blood pressure. Like-
ling blood pressure, including the sympathetic nervous sys-
wise, Manzini and Bacciarelli [18] found that, in the deoxy-
tem, the renin-angiotensin system, endothelin, and oxidative
corticosterone acetate (DOCA)-salt hypertensive model, hy-
stress. Moreover, putative endogenous agonists of the
TRPV1 and perspectives of drug development are also dis-
pertension was of quicker onset and of greater magnitude in
cussed.
the rats pretreated with capsaicin, indicating that capsaicin-

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Neural Control of Blood Pressure
Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1 39
thetic nerve activity. The DRG contains cell bodies of
CGRP-positive neurons, which send axons to peripheral tis-
sues (i.e., hearts, blood vessels and kidneys) and centrally to
laminae I/II of the dorsal horn of the spinal cord. These af-
ferents synapse with the intermediolateral cell column of the
spinal cord, which contains the sympathetic preganglionic
neurons. This connection provides morphological evidence
supporting that primary afferents may influence sympathetic
nerve activity at the level of the spinal cord, and thus regu-
late cardiovascular function (Fig. 4). Likewise, evidence
shows that CGRP may modulate sympathetic nervous activ-
ity centrally or at the peripheral sites. Fisher et al. [29]
Fig. (3). Systolic blood pressure in vehicle (CON) or capsaicin
(CAP)-treated rats fed a normal (NS, 0.5% of sodium) or high (HS,
4% of sodium)-sodium diet for 14 days. Systolic blood pressure
was measured by the tail-cuff method in the conscious state on day
14. Neonatal rats received vehicle (5% ethanol, 5% Tween-80 and
90% saline) or CAP (50 mg/kg, dissolved in 5% ethanol, 5%
Tween-80 and 90% saline) on the first and second days of life. Val-
ues are mean ± SE (n = 6-8 rats). *P<0.05 versus CON-NS, CON-
HS, and CAP-NS.
sensitive sensory nerves may constitute one of antihyperten-
sive mechanisms to prevent development of DOCA-salt hy-
pertension. Indeed, the studies by Supowit et al. [19] re-
ported that bolus injection of CGRP8-37, a CGRP receptor
antagonist, produced a dose-dependent increase in mean ar-
terial pressure in DOCA-salt hypertensive rats, suggesting
that CGRP released by sensory nerves plays a protective role
in preventing the development of hypertension in this model.
THE SYMPATHETIC NERVOUS SYSTEM

The cardiovascular tissues and the kidney are richly in-
nervated by post-ganglionic sympathetic fibers. In the kid-
ney, sympathetic nerves innervate the afferent and efferent
renal arterioles, juxtaglomerular apparatuses, proximal renal
tubules, loops of Henle, and renal distal tubules [20, 21].
Fig. (4). Schematic illustration of neural control of cardiovascular
Therefore, the efferent renal sympathetic nerves may affect
function and blood pressure. In addition to classic baroreflexes,
the function of the renal vasculature, renin release, and so-
sensory nerves activated by mechanical or chemical stimuli trans-
dium and water excretion [22, 23]. Evidence exists suggest-
mit electrical signals to the central nervous system and release sen-
ing that the sympathetic nervous system may serve as initiat-
sory neurotransmitters, which, in coordination with the sympathetic
ing as well as sustaining mechanisms responsible for ele-
nervous system, regulate cardiovascular function. PVG, paraverte-
vated arterial pressure in experimental animals and humans.
bral chain ganglia; MCG, middle cervical ganglion; ARG, aorti-
corenal ganglion; DRG, dorsal root ganglia; CGRP, calcitonin
In a number of experimental models of hypertension includ-
gene-related peptide; SP, substance P; NKA, neurokinin A.
ing spontaneously hypertensive [24, 25] and DOCA-salt hy-
pertensive rats [26] and essential hypertensive humans [27,
reported that intracerebroventricular administration of CGRP
28], there is an increase in sympathetic nerve activity, which
enhanced sympathetic nerve activity and increased blood
appears to contribute significantly to the development of
pressure, suggesting that CGRP acts in the central nervous
hypertension through modulation of renal vascular resistance
system to stimulate noradrenergic sympathetic outflow. In
and urinary sodium excretion.
contrast, the studies by Ralevic and Takenaga et al. [30, 31]

Traditionally, the role of the sensory nervous system in
have shown that vasoconstriction in response to adrenergic
the regulation of sympathetic outflow has been thought to be
nerve stimulation is potentiated significantly by capsaicin-
mediated via baroreflex mechanisms. It has become apparent
induced denervation of sensory nerves or by blockade of the
recently that somatic capsaicin-sensitive sensory nerves and
CGRP receptor with CGRP8-37 administered into perfused
their neuropeptides exert a regulatory influence on sympa-
mesenteric vascular beds, suggesting that CGRP suppresses

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40 Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1
Wang and Wang
adrenergic nerve-induced vasoconstriction via both prejunc-
stasis through direct and indirect actions on renal excretory
tional and postjunctional mechanisms. Several studies have
function. The mechanisms responsible for regulation of the
shown that genetic deletion of CGRP leads to increased
body fluid volume contribute to long-term blood pressure
blood pressure associated with elevated sympathetic nervous
regulation. Inappropriately high Ang II levels reduce renal
activity [32, 33]. These results provide evidence supporting
excretory function and impair pressure natriuresis, thereby
that CGRP inhibits sympathetic nerve activity. Further stud-
necessitating increased arterial pressure to maintain sodium
ies are necessary to clarify the mechanisms responsible for
balance [41, 42]. In addition, Ang II stimulates the synthesis
CGRP-induced inhibition of sympathetic nerve activity.
of preproendothelin [43] and produces oxidative stress [44].
Thus, in addition to its direct effects, activation of the RAS

We found that sympathectomy produced by administra-
may stimulate the production of endothelin and oxidative
tion of guanethidine prevented the development of salt-
stress to further increase blood pressure.
sensitive hypertension induced by sensory nerve degenera-
tion [34]. The finding suggests that enhanced sympathetic

We explored the role of the RAS in the development of
nerve activity may contribute to the increase in blood pres-
salt-sensitive hypertension induced by neonatal sensory den-
sure in capsaicin-pretreated rats fed a high salt diet, and that
ervation [35]. Losartan, a type 1 Ang II receptor antagonist,
capsaicin-sensitive sensory nerves may normally inhibit
was given to capsaicin-pretreated rats fed a high salt diet. We
sympathetic nerve activity, especially during high salt intake.
found that systolic blood pressure and mean arterial pressure
We also found, however, that blockade of the 1-adreno-
were higher in capsaicin-treated rats fed a high salt diet
ceptor with prazosin was not effective in preventing the de-
compared to capsaicin-treated rats fed a high salt diet plus
velopment of salt-induced hypertension in capsaicin-
losartan or hydralazine, a nonspecific vasodilator. Although
pretreated animals [35]. The reasons for the ineffectiveness
losartan and hydralazine decreased blood pressure, these
of prazosin in decreasing blood pressure in the later study are
drugs did not improve the impaired natriuretic response to
unknown, but may be due to: (1) the dose of prazosin used
salt load in capsaicin-pretreated rats [35]. These results sug-
was not high enough to decrease blood pressure in this
gest that losartan and hydralazine may lower blood pressure
model, even though the same dose caused reduction in blood
via direct vasodilatory mechanisms, rather than those that
pressure in spontaneously hypertensive rats [36]; (2) 1-
improve the impairment of urinary sodium and water excre-
adrenoceptors were necessary for the development of salt-
tion. These findings suggest but not provide proofs for an
sensitive hypertension, a possibility supported by findings of
interaction between capsaicin-sensitive sensory nerves and
Osborn et al. [37] showing that blockade of the 1-adreno-
the RAS. The interaction between these two systems was
ceptor with prazosin renders rats salt-sensitive and leads to
further investigated in Ang II-induced hypertensive rats, and
the development of salt-sensitive hypertension; and (3) the
the results showed that sensory denervation by capsaicin-
sympathetic nervous system might contribute to the devel-
pretreatment exacerbated the development of hypertension
opment of salt-sensitive hypertension in neonatally capsaicin-
induced by subpressor infusion of Ang II [45]. Moreover, we
pretreated rats via a non- 1-adrenoceptor mechanisms.
found that sensory denervation in subpressor Ang II-infused
rats resulted in a decrease in water and sodium excretion
THE RENIN-ANGIOTENSIN-ALDOSTERONE SYS-
[45], a result that was different from unchanged sodium and
TEM
water balance in animals treated with small or subpressor

Pressure natriuresis is a key component to regulate the
doses of Ang II alone [45, 46]. These findings suggest that
body fluid volume. In all forms of hypertension, there is a
capsaicin-sensitive sensory nerve innervation preserves the
shift of renal pressure natriuresis that requires increased arte-
renal excretory function in hypertension induced by subpres-
rial pressure to maintain sodium and water balance [38, 39].
sor infusion of Ang II. The notion is supported by the evi-
The renin-angiotensin system (RAS) is a powerful hormone
dence showing that renal nerves promote sodium excretion
system regulating blood pressure and body fluid volumes, as
in hypertension induced by Ang II infusion [47]. These stud-
evidenced by the effectiveness of various RAS blockers in
ies provide a rationale for future investigation of sensory
reducing arterial pressure and protecting against cardiovas-
nerve control of the renal function under pathophysiological
cular and renal injury in many forms of hypertension [40]. In
conditions.
most conditions, activation of the RAS occurs as a compen-

Plasma renin activity and plasma aldosterone level are
satory response to volume depletion or circulatory depres-
significantly higher in sensory-denervated rats fed a high diet
sion. These actions help to return body fluid volumes and
compared to sensory nerve-intact rats fed a high salt diet
arterial pressure toward normal levels. Angiotensin II (Ang
[48]. To define the influence of altered aldosterone levels,
II), the effector of the RAS, produces antinatriuretic actions
spironolactone, a selective aldosterone receptor antagonist,
via increasing renal tubular reabsorption rather than reducing
was given to capsaicin-pretreated rats fed a high salt diet. We
glomerular filtration rate (GFR), except in pathophysiologi-
found that spironolactone normalized blood pressure and
cal conditions in which Ang II contributes to glomeruloscle-
renal excretory function in capsaicin-pretreated rats fed a
rosis and loss of nephron function. Ang II increases tubular
high salt diet [48]. These data indicate that the circulating
reabsorption by direct as well as indirect effects such as
renin-angiotensin-aldosterone system is insufficiently sup-
stimulation of aldosterone [41] to decrease sodium excretion
pressed by salt load in sensory-denervated rats, resulting in
to very low levels. The long-term effects of the RAS on
an increase in salt sensitivity in terms of blood pressure regu-
blood pressure are closely intertwined with volume homeo-

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Neural Control of Blood Pressure
Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1 41
lation. It is well established that aldosterone increases the
the endothelin system is involved in the development of hy-
reabsorption of sodium and the secretion of potassium by
pertension.
regulating the Na+-K+-ATPase and epithelial Na+ channels

In salt-sensitive hypertension induced by sensory nerve
located in a variety of tissues, including collecting ducts of
degeneration, we found that increased blood pressure oc-
the kidney, sweat glands, salivary glands, and the intestine
curred in association with an increase in plasma ET-1 levels
[49, 50]. Moreover, aldosterone enhances ion permeability in
[64]. Moreover, blockade of the ET
vascular smooth muscles and amplifies the local vasocon-
A receptor with AB T-
627, a highly selective ET
strictor system, actions that have been suggested to play a
A receptor antagonist, prevented
the development of hypertension in this model, albeit it did
role in the mineralocorticoid-salt model [51]. It is conceiv-
not alleviate impaired renal function in capsaicin-treated rats
able therefore that elevated aldosterone levels play a role in
fed a high salt diet [64]. In this study, ABT-627 was given
the development of hypertension in this model, possibly via
by oral gavage twice per day, a stress leading to water and
renal dependent and independent mechanisms. Further stud-
sodium retention which may offset the beneficial effect of
ies are necessary to define the mechanisms underlying aldos-
this drug on improving renal function. Indeed, our recent
terone action in this model.
studies showed that ABT-627 when given in drinking water
THE ENDOTHELIN SYSTEM
prevents the development of hypertension and improves re-
nal hemodynamics and excretory function in sensory nerve

The endothelin system is a family of 3 distinct 21-residue
degenerated rats fed a high salt diet [65]. These results indi-
peptides, including ET-1, ET-2, and ET-3. ET-1 is synthe-
cate that elevated endogenous ET-1 and subsequent activa-
sized by endothelial cells, and is a potent vasoconstrictor
tion of the ET
[52]. The physiological actions of ET-1 are mediated by at
A receptors exert antinatriuretic actions that
may contribute to increased salt-sensitivity of arterial pres-
least two receptor subtypes including ETA and ETB recep-
sure in the sensory denervated model or in general.
tors. The ETA receptors, expressed mainly in smooth muscle
cells of blood vessels, contribute to the vasoconstriction re-

The fact that plasma ET-1 levels are increased in sensory
sponse to ET-1 [53]. Activation of ETB receptors induced by
nerve-denervated rats fed a high salt diet suggests that cap-
ET-1 mediates numerous pathophysiological responses in-
saicin-sensitive sensory nerves and their neurotransmitters
cluding smooth muscle contraction, vasodilation, and clear-
may normally inhibit the synthesis and release of ET-1 [64,
ance of circulating ET-1 [53]. Moreover, ET-1 amplifies the
65]. In contrast, several lines of evidence indicate that ET-1
contractile response to other vasoactive agents, including
leads to a release of sensory neurotransmitters which play a
norepinephrine and serotonin [54]. Consistent with these
compensatory role in preventing ET-1-induced elevation in
findings, ET-1 potentiates sympathetically mediated vaso-
blood pressure. It has been reported that CGRP acts as a
constriction in hypertensive patients such that a positive cor-
compensatory vasodilator to attenuate the increase in blood
relation exists between ET-1-induced vasoconstriction and
pressure in DOCA-salt hypertension [19]. Increased neu-
blood pressure [53].
ronal expression of CGRP and presumably the release of this

In addition to blood vessels, the kidney is one of the most
peptide suggest that circulating and/or autocrine/paracrine
sensitive organs to ET1 stimulation. ET-1 is produced in the
factors such as elevated levels of endothelin may stimulate
kidney and both of its receptor subtypes, ET
the long-term synthesis and release of CGRP from sensory
A and ETB, are
present in the kidney [55]. Thus, ET-1 possesses potent and
afferents in DOCA-salt hypertension [60, 62]. Indeed, Gokin
complex actions in the kidney, whereby it causes renal vaso-
et al. [66] reported that peripheral administration of ET-1
constriction and regulates renal sodium and water excretion.
induces nocifensive behavior that is reversible by admini-
It is well established that ET-1 is a potent constrictor of both
stration of an ETA receptor antagonist, suggesting that ETA
afferent and efferent arterioles and causes a decrease in renal
receptors are present in sensory afferent fibers. This view is
blood flow and GFR, leading to a reduction in urine flow and
further supported by studies from Pomonis et al., showing
sodium excretion [55, 56]. Both receptor subtypes have been
that ETA receptor-immunoreactivity is found in CGRP-
reported to contribute to renal vasoconstriction [57]. How-
containing sensory neurons in DRG, whereas ETB receptor-
ever, activation of ET
immunoreactivity is observed in DRG satellite cells or
B receptors expressed in renal distal
tubules causes opposite effects and promotes natriuretic and
Schwann cells [67]. The fact that colocalization of ETA and
diuretic actions of ET-1 [57].
CGRP in sensory nerve fibers supports the notion that ET-1-
induced CGRP release is mediated by activation of the ETA

ET-1, when administered on long-term bases, increases
receptor. Moreover, recent studies from our laboratory have
sodium reabsorption in the kidney and elevates blood pres-
shown that, in addition to ETB receptor-mediated vasodila-
sure [58, 59]. It is well established that the endothelin system
tion, chronic infusion of ET-1 at the pathophysiological con-
is activated in salt-dependent models of hypertension, in-
centration leads to an ETA-dependent CGRP release, which
cluding DOCA-salt hypertensive rats and genetic Dahl salt-
may play a counterregulatory role in preventing ET-1-
senitive hypertensive rats [60, 61]. In these models as well as
induced increases in blood pressure [68].
a subpopulation of hypertensive patients, plasma ET1 levels
are elevated and production of ET-1 in vascular endothelial

Although salt-sensitive hypertension induced by sensory
cells is enhanced [62, 63]. Consistent with these findings,
nerve degeneration is characterized by an increase in plasma
endothelin receptor antagonists lower blood pressure in these
ET-1 levels, the mechanisms responsible for elevated ET-1
models [60, 61]. These findings provide strong evidence that
levels are unclear. It has been reported that ETB receptors are

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42 Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1
Wang and Wang
involved in ET-1 clearance [57]. However, elevated plasma
salt diet [48, 64, 65]. It is well-established that Ang II and
ET-1 levels in sensory denervated rats fed a high salt diet
ET-1 stimulate superoxide formation via activating NAD(P)H
were unaffected by blockade of the ETB receptors [64], sug-
oxidases [44, 74]. Therefore, the increase in superoxide pro-
gesting that 1) the elevated plasma ET-1 levels are not medi-
duction may be derived from activation of the ET and Ang II
ated by the ETB receptors; or 2) ETB receptors are down-
systems in this model. Although our findings suggest that
regulated in sensory denervated rats leading to ineffective-
ROS may contribute to the development of salt-sensitive
ness in blockade of the ETB with its antagonists. Moreover, it
hypertension induced by sensory nerve degeneration, treat-
is known that the endothelin system can be upregulated by
ment with tempol is ineffective in lowering blood pressure in
Ang II [43], and ETA receptors have been shown to mediate
this model [81]. This is in contrast to the effect of mem-
Ang II-induced hypertension in animal studies [69]. Like-
brance-targeted forms of SOD and other antioxidants on
wise, endothelin causes oxidative stress, and endothelin pro-
blood pressure in hypertension [75-79]. Although it is un-
duction has been shown to be increased in response to oxida-
clear why tempol is unable to lower blood pressure in this
tive stress [70]. Therefore, elevated plasma endothelin levels
model, there are alternative explanations for these results: 1)
in this model could be the result of increases in Ang II and/or
the influence of tempol on blood pressure wanes over time;
oxidative stress.
2) tempol is ineffective in lowering superoxide production
and in improving renal function even though superoxide
REACTIVE OXYGEN SPECIES
production in mesenteric arteries is inhibited by tempol; and
Several lines of evidence indicate that oxidative stress
3) as an SOD mimetic, tempol converts superoxide to hydro-
plays an important role in cardiovascular dysfunction, in-
gen peroxide (H2O2) that is subsequently converted to H2O
cluding ischemic heart disease, chronic heart failure, and
by catalase and glutathione peroxide (GPx). It is possible
diabetes mellitus. Oxidative stress is a state in which excess
that tempol leads to more H2O2 production in the kidney than
reactive oxygen species (ROS) overwhelm endogenous anti-
that can be handled by the endogenous H2O2-scavenging
oxidant systems. Superoxide (O ·-
2 ), formed by the univalent
systems. It has been reported that chronic increases in H2O2
reduction of oxygen, is one of the most important ROS af-
levels in the renal medulla result in hypertension [82].
fecting the cardiovascular system [71]. Potential sources of
Moreover, the studies by Michael et al. [83] indicate that
vascular superoxide production include NAD(P)H-dependent
increased renal H2O2 levels may limit the ability of tempol to
oxidases, xanthin oxidase, lipoxygenase, mitochondrial oxi-
lower blood pressure in salt-sensitive hypertension. Further
dase, and NO synthases [71]. NAD(P)H oxidases appear to
studies are necessary to clarify the role of increased superox-
be the principal source of superoxide production in several
ide in the development of hypertension in sensory-denervated
animal models of vascular disease [44, 72]. This is due to the
rats fed a high salt diet.
fact that NAD(P)H oxidase protein abundantly expresses in
TRPV1 RECEPTORS AND ANANDAMIDE
the cardiovascular system [73], and is responsive to a variety
of agonists, such as angiotensin and endothelin-1 [44, 74].

Anandamide, isolated from porcine brain in 1992 [84], is
one of the endogenous ligands for the cannabinoid (CB) re-

ROS has been implicated in the development of hyper-
ceptor. Cannabinoids are known to elicit neurobehavioral as
tension and other pathologic processes including ischemic
well as cardiovascular effects. The biological effects of can-
heart disease and chronic heart failure, effects involving in-
nabinoids are mediated by specific receptors, of which two
activation of NO by superoxide in the vasculature and the
subtypes have been identified by molecular cloning. The
kidney and H2O2-induced vessel modeling. ROS is increased
CB1 receptors express abundantly in both the central nerv-
in several hypertensive models including spontaneously hy-
ous system and peripheral tissues [85], whereas CB2 recep-
pertensive rats, 2-kidney, 1-clip hypertensive rats, Ang II-
tor expression is restricted to the immune system [86]. Given
infused hypertensive rats, DOCA-salt hypertensive rat, and
their profound cardiovascular effects in humans and animals,
Dahl salt-sensitive hypertensive rats [75-79]. Furthermore,
there is ever-increasing interest in endogenous cannabinoids.
administration of antioxidants, cell-permeable superoxide
Recent studies show that anandamide and its analogs cause a
dismutase (SOD) mimetic tempol, or genetic deletion of
prolonged hypotension and bradycardia in anesthetized nor-
NAD(P)H oxidase partially normalizes blood pressure in
motensive rats, rats fed a high salt diet, or spontaneously
these models of hypertension [75-80]. These observations
hypertensive rats (SHR) [87-89]. Despite the potent cardio-
strongly suggest that ROS contributes to the onset and main-
vascular effects, relatively little is known about the mecha-
tenance of hypertension.
nisms underlying anandamide-induced cardiovascular ac-
We found that salt-sensitive hypertension induced by
tions. CB1 receptors have been found in the nucleus of the
sensory nerve degeneration is associated with an increase in
solitary tract and in the dorsal motor nucleus of the vagus
superoxide production and a compensatory elevation in
[90], suggesting that CB1 expressed in the brain may be in-
MnSOD levels in mesenteric resistant arteries, indicating
volved in the regulation of cardiovascular function. In addi-
that ROS is increased in this salt-sensitive hypertensive
tion, accumulating evidence shows that cannabinoids pre-
model [81]. The mechanisms responsible for the increase in
synaptically inhibit the release of noradrenaline from post-
ROS are unclear. As discussed above, plasma ET-1 levels
ganglionic sympathetic neurons [91]. Therefore, cannabi-
are increased and the renin-angiotensin-aldosterone system is
noids may influence cardiovascular function via modulating
insufficiently inhibited in sensory denervated rats fed a high
autonomic outflow in both the central and peripheral sites.

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Neural Control of Blood Pressure
Cardiovascular & Haematological Disorders-Drug Targets, 2007, Vol. 7, No. 1 43
The studies by Varga et al. have shown that anandamide-
sion, however, remain poorly understood. There is accumu-
induced prolonged hypotension is attenuated by pretreatment
lating evidence showing that a defect in the sensory nervous
with cervical spinal transection or by -adrenoceptor and
system exists in Dahl salt-sensitive hypertensive and sponta-
cannabinoid receptor antagonists, indicating that the sympa-
neously hypertensive rats [98, 99]. The Dahl salt-sensitive
thetic nerve system may be involved in the depressor re-
model is believed to best approximate the pathology associ-
sponse [92]. Moreover, it is evident that there is no centrally
ated with hypertension in African Americans [100, 101]. It is
elicited effect of anandamide on the firing rate of presympa-
conceivable that sensory nerve dysfunction may contribute
thetic sympathoexcitatory neurons in the rostral ventrolateral
to the development of hypertension in these models of hy-
medulla oblongata and of splanchnic sympathetic nerve fi-
pertension. Given that the sensory nervous system, including
bers [87]. These results suggest that peripheral actions of
TRPV1 receptors expressed in sensory nerves, sensory neu-
anandamide appear to be predominating in cardiovascular
rotransmitters, and their receptors, plays a counter regulatory
regulation.
role in attenuating salt-induced increases in blood pressure
[15, 88], it is reasonable to speculate that agents that modu-

Recently, several lines of evidence in vitro and in vivo
late activity of the sensory nervous system may be beneficial
have shown that anandamide-induced cardiovascular actions
in treating hypertension as well as in reducing the long-term
may be mediated by its activation of the TRPV1 receptor
complications resulting from hypertension. It is well estab-
[88, 89, 93]. Several studies report that anandamide displays
lished that TRPV1 is activated by the plant extract capsaicin.
a highly structural similarity to the vanilloids [94, 95]. The
Moreover, capsaicin produces a profound hypotensive effect
studies by Zygmunt et al. [93] demonstrate that anandamide
in SHR and in rats fed a high salt diet, suggesting that activa-
and its analogue methanandamide (MethA) act as agonists at
tion of the TRPV1 may be an efficacious means in prevent-
the recombinant rat TRPV1 receptors. These findings are
ing the development of hypertension [88, 89]. Clinically,
further confirmed by Smart et al. using the human TRPV1
repeated topical applications of cream containing capsaicin
clone [96]. Furthermore, Wagner et al. [97] have demon-
are effective for the relief of chronic pain including posther-
strated that SR141716A, a selective CB1 receptor antagonist,
petic neuralgia and neuropathy [102, 103]. These inhibitory
fails to inhibit anandamide-induced vasodilation in endothe-
actions of topical capsaicin are thought to be primarily due to
lium-denuded mesenteric preparations from rats. This study
functional desensitization of nociceptive neurons. Systemic
suggests that anandamide-induced mesenteric vasodilation is
applications of capsaicin in humans are rare due to the irri-
partially mediated by an SR-141716A-resistant action on
tant nature of this exogenous compound. However, of grow-
vascular smooth muscle. Zygmunt and colleagues [93] dem-
ing interest is the compelling evidence that TRPV1 receptors
onstrate that in isolated rat hepatic, rat mesenteric, and
expressed in sensory nerves may be activated by an array of
guinea pig basilar arterial preparations, anandamide-induced
endogenous molecules including anandamide and other lipid
relaxation is almost completely blocked either by the selec-
metabolites [88, 89, 93]. In light of the fact that high sodium
tive TRPV1 receptor antagonist, capsazepine (CAPZ), or by
intake increases anandamide levels as well as the depressor
the selective CGRP receptor antagonist, CGRP8-37, but not by
response to exogenous anandamide [88], we propose that
SR141617A. These results suggest that the TRPV1-mediated
anandamide may serve as an endovanilloid compound able
release of CGRP from sensory nerves is responsible for the
to stimulate TRPV1 leading to prevention of salt-induced
anandamide-evoked vasorelaxation. In animal studies, we
increases in blood pressure. It follows that manipulations
have demonstrated that the MethA-induced depressor effect
modulating anandamide production or metabolism may alter
in SHR rats is attenuated by blockade of the TRPV1 receptor
TRPV1 function and therefore blood pressure. Our results
with CAPZ, indicating that activation of the TRPV1 receptor
may provide a rationale for the search of novel endogenous
is involved in anandamide-induced hypotensive effects [89].
and/or exogenous TRPV1 agonists and antagonists for the
Moreover, the latest studies from our laboratory have shown
treatment of salt-dependent hypertension and may improve
that plasma anandamide concentrations are increased during
our understanding of the molecular mechanisms leading to
high sodium intake (unpublished data), and that MethA
increased salt sensitivity especially in diverse ethnic groups.
causes an enhanced and dose-dependent depressor effect in
high salt-treated rats which can be attenuated by a TRPV1
ACKNOWLEDGEMENT
receptor antagonist [88]. These findings support the concept

This work was support in part by National Institutes of
that activation of the TRPV1 receptor induced by endoge-
Health (grants HL-57853, HL-73287, and DK67620) and
nous anandamide may play a compensatory role in attenuat-
grants from Michigan Economic Development Corporation.
ing the increase in blood pressure during high sodium intake.
The authors would like to express their gratitude to all re-
CLINICAL RELEVANCE AND CONCLUSION
search fellows, visiting scientists, and students who have
participated and contributed to the aforementioned studies.

It is estimated that 65 million individuals in the United
Dr. Donna H. Wang is an American Heart Association Es-
States suffer from hypertension. High salt intake has been
tablished Investigator.
implicated in the pathogenesis of hypertension, parti