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Mammalian transient receptor potential (TRP) channels consist of
six related protein sub-families known as TRPV, TRPC, TRPM, TRPP,
TRPML, and TRPA[1]. These channels are widely distributed
and involved in sensing local stimuli ranging from changes in hemodynamics
to pH and osmo-larity. The TRPV1 channel, a member of the TRPV sub-family,
was identified by expression cloning using the "hot" pepper-derived
vanilloid compound capsaicin as a ligand. TRPV1 is therefore referred
as the vanilloid receptor (VR1) or the capsaicin receptor. Capsaicin
as well as other closely related vanilloid substances are principal
constituents in the hot chilli peppers and responsible for the pungency
of these spices[2].
Over the last several centuries, knowledge about the physiological
actions of capsaicin has grown and capsaicin has become a powerful
tool, as will be described, for studying mechanisms underlying hypertension.
Ever since its isolation in the mid-nineteenth century, capsaicin
has been documented to act on sensory fibers with neuroselectivity[3,4].
Nelson elucidated the structure of capsaicin, reporting it as 8-methyl-vannillyl-6-noneamide,
an acylamide derivative of homovanillic acid[5]. The
compound consists of three functional moieties: vannilyl, acylamide,
and alkyl[2]. Jancso later showed that capsaicin-sensitive
nerve endings could be stimulated as well as destroyed by a sufficiently
high dose of capsaicin[6]. The neurotoxicity effect of
capsaicin is of paramount importance, for reasons that will become
clear, to neurobiologists using capsaicin sensitive-sensory nerve
degeneration to study blood pressure regulation. The review that
follows outlines the advances that have been made since Jancso's
publications, with regard to mechanisms of capsaicin's action, cardiovascular
effects of select neuropeptides released by a subset of capsaicin-sensitive
primary afferent neurons (CSPAN) innervating cardiovascular and
renal tissues, and pathophysiologic mechanisms of hypertension elucidated
by capsaicin sensitive sensory-nerve degeneration. Capsaicin pharmacology
and the nature of capsaicin-sensitive sensory nerves are discussed
in greater detail in a number of other excellent scholarly reviews[7-9].
This review is restricted to a discussion of the effects of capsaicin
on the cardiovascular system. Other authors have reviewed the effects
of capsaicin on the somatosensory, respiratory, thermoregulatory,
and gastrointestinal systems[10-14].
VR1 positive sensory neurons
VR1-positive sensory neurons refer to a subset of primary afferent
neurons that express the VR1 receptors which can be activated by
capsaicin. The pharmacological property of sensitivity to capsaicin
distinguishes these afferent neurons, mostly having unmyelinated
(C fibers) or thinly myelinated axons (A¦Ä fibers), from other
afferent neurons[15].
Maggi[15] has described the functional anatomy of the
VR1-positive primary afferent neuron by identifying four sites from
which neurotransmitter release may occur: (i) central terminals
of the afferent neuron in contact with second-order neurons in the
CNS; (ii) terminals distributed in the prevertebral ganglia; (iii)
peripheral terminals distinct from the terminal at which the sensory
stimulus is applied; and (iv) the same peripheral terminal at which
the sensory stimulus is applied. Neurotransmitter release at sites
(i) and (ii) accounts for the sensory function of CSPAN and is central
to perception of somatic and visceral pain. In contrast, and as
implied by neuropeptide release from peripheral terminals (iii)
and (iv), CSPAN nerve endings not only serve as sensory receptors,
but also as effector sites from which neurotransmitters are released.
Thus, neurotransmitter release from sites (iii) and (iv) accounts
for the "sensory-efferent" function of CSPAN, with release
from site (iv) not even requiring neuronal conduction[15].
Accordingly, Maggi and Meli[11] have termed release from
site (iv) the "sensory receptor potential-coupled efferent
response." Local sensory stimuli that may induce neurotransmitter
release are varied and include nerve growth factor[16],
vascular wall tension[17], the sympathetic nervous system[18],
bradykinin[19], and endothelin[20].
Efferent function of VR1-positive sensory neurons
VR1-positive sensory neurons have a dual function: sensory perception
and sensory efferent function. Binding of capsaicin and capsaicin
agonists to VR-1 leads to neuropeptide release from a subpopulation
of neuropeptide-containing primary afferent neurons[15].
Binding to this receptor opens a receptor-operated permeable cation
channel[21-25] that ultimately results in the influx
of sodium and calcium ions. Sodium influx is sufficient for afferent
impulse conduction. In sharp contrast, calcium influx, and thus
extracellular calcium, is prerequisite for neuropeptide release.
Without extracellular calcium, sensory neuropeptides are no longer
released from sensory nerve endings when these endings are depolarized[15].
Given that the neuroselectivity of capsaicin is a reflection of
the selective expression of the VR1 on a subpopulation of primary
afferent neurons, a closer look at the VR1 is warranted. Initial
evidence supporting a capsaicin-binding site on a subset of primary
afferent neurons came from observations that capsaicin analogues
are able to exert similar functional changes[26,27].
Additional support came from experimentation with resiniferatoxin,
a phorbol ester derivative that has been shown to exhibit structural
similarity [28,29] and densensitizing and excitatory
properties homologous to those exhibited by capsaicin, albeit at
1000-fold lower doses[28-30]. Definitive support for
the presence of a chemical moiety capable of binding to capsaicin
and related agonists came with the development of capsazepine, experimentally
shown to act as a competitive antagonist of vanilloid binding and
activity[31]. The VR-1 has been reviewed in greater detail
in an authoritative review by Caterina and Julius[32].
Concerning the nature of transmitters released from VR1-positive
sensory neurons, Maggi and Meli[15] have reported that
at least the following 12 different types of transmitters are present
in capsaicin-sensitive sensory neurons: substance P (SP), neurokinin
A, neuropeptide K, eledoisin-like peptide, somatostatin, vasoactive
intestinal polypeptide, cholecystokinin-octapeptide, calcitonin
gene-related peptide (CGRP), galanin, corticotrophin-releasing factor,
arginin vasopressin, bombesin-like peptides. These authors also
report that multiple neuropeptides can be simultaneously released
from VR1-positive sensory nerve endings. However, different neuropeptides
may be preferentially released as a function of stimulus intensity[33].
It has been shown that plasma concentrations of CGRP rise transiently
after administration of capsaicin in adult rats[3,4].
Given that capsaicin exerts its action through release of neuropeptides,
acute administration of capsaicin produces functional changes related
to the activity of the released neuropeptides[35]. In
contrast, and of significance to elucidating mechanisms underlying
hypertension, capsaicin administered systemically at a dose of 50 mg/kg
of body weight to neonatal rats or mice leads to an irreversible
loss of more than 80% of small-diameter sensory neuron cell bodies[36-41].
These observations indicate that high doses of capsaicin lead to
neurotoxic effects including substantial depletion of stores of
neuropeptides within VR-1 positive sensory neuron.
Innervation of cardiovascular tissue by VR1-positive sensory
nerves
VR1-positive sensory nerves are found around blood vessels in virtually
all vascular beds. CGRP, often co-localized with SP, is found in
nerve endings of a subset of these sensory nerves[42-46].
Synthesis of these neuropeptides occurs in the dorsal root ganglia
which contain cell bodies of the capsaicin-sensitive sensory nerves.
CGRP, co-localized with SP, is also found in a subpopulation of
VR1-positive sensory nerves innervating the hearts of rats, guinea
pigs, and humans, though in a much lower density than around blood
vessels[43].
CGRP is a potent vasodilator that also has positive chronotropic
and ionotropic effects[43]. The coronary vasculature
is a particularly susceptible target of the vasodilatory action
of CGRP[47,48]. Of significance to understanding the
pathogenesis of hypertension, systemic administration of CGRP decreases
blood pressure in normotensive animals, normotensive humans, and
spontaneously hypertensive rats[43,44]. This decrease
is produced via peripheral arterial dilation mediated through nitric
oxide-dependent and nitric oxide-independent mechanisms[43].
The fact that bolus injection of CGRP8-37, a CGRP receptor
antagonist, produces dose-dependent increases in mean arterial pressure
in deoxycorticosterone-salt hypertensive rats indicates that CGRP-induced
vasodilation may play a compensatory role in this model[49].
VR1-positive sensory nerves and established models of hypertension
At least two hypertensive models have been used for defining the
role of VR1-positive sensory nerves. One is the one-kidney wrap
(1K-WRAP) hypertensive model and the other the deoxycorticosterone
(DOCA)-salt hypertensive model. Intrathecal administration of capsaicin
to adult rats was used to deplete SP and CGRP within central processes
of afferent renal nerves (ARN) within selective laminae of the dorsal
horn for determining whether SP and/or CGRP localized in ARN play
a role in the development of 1K-WRAP hypertension or DOCA-salt hypertension[50].
Capsaicin treatment enhanced the development of 1K-WRAP hypertension,
considering that systolic blood pressure was greater in 1K-WRAP
rats pretreated with capsaicin compared with vehicle-treated 1K-WRAP
rats[50]. However, capsaicin pretreatment had no effect
on systolic blood pressure in DOCA-salt rats, suggesting that the
depletion of sensory neurotransmitters from ARN by capsaicin does
not exacerbate DOCA-salt hypertension. Indeed, these authors concluded
that "ARN did not play a major role in the development of DOCA-salt
hypertension."[50]
Manzini and Bacciarelli[51] performed a similar study
in which the effect of neonatal degeneration of VR1-positive sensory
nerves on the development of DOCA-salt hypertension was investigated.
As expected by the degeneration of sensory neurons in capsaicin-pretreated
animals, substance P-like immunoreactivity was virtually undetectable
in capsaicin-pretreated animals and blood pressure was much less
responsive to acute administration to capsaicin as compared to control
animals. DOCA-salt induced-hypertension was of quicker onset and
of greater magnitude in the animals pretreated with capsaicin. Hypertensive
rats pretreated with capsaicin also had a greater incidence of cardiac
necrosis. These authors, in contrast to Burg et al, concluded
that capsaicin-sensitive sensory fibers may underlie antihypertensive
mechanisms and play a protective role in preventing the development
of DOCA-salt hypertension[51].
VR1-positive sensory nerves and increased salt sensitivity
Though studies by Burg et al[50] and Manzini
and Bacciarelli[51] have shown that VR1-positive sensory
nerves are implicated in blood pressure regulation, these investigations
have not shown whether impairment of the sensory nervous system
is sufficient to produce hypertension. We showed for the first time
in 1998 that neonatal degeneration of VR1-sensitive sensory nerves
rendered an adult rat salt-sensitive[52]. We administered
50 mg/kg capsaicin or vehicle subcutaneously to newborn Wistar
rats on the first and second days of life, and a high or normal
sodium diet was given immediately following the weaning period.
We found that neonatal treatment with capsaicin led to elevation
of blood pressure in rats fed a high sodium diet, but not in those
fed a normal sodium diet. High salt intake increased urine volume
and sodium excretion in both vehicle and capsaicin treated rats.
However, these parameters were significantly lower in capsaicin
treated rats fed a high-salt diet compared to vehicle treated rats
fed a high-salt diet. These results suggest that capsaicin neonatal
treatment might impair renal function when rats are loaded with
salt.
Role of the renin-angiotensin-aldosterone system (RAAS)
To define the molecular mechanisms underlying sensory nerve function
involved in the pathogenesis of salt-sensitive hypertension, we[53]
subsequently explored the role of the RAAS in the aforementioned
salt-sensitive hypertensive model induced by sensory denervation.
Capsaicin plus high-salt-treated rats were given losartan (a type
I angiotensin II receptor blocker), prazosin (a selective ¦Á1-adeno-receptor
blocker), or hydralazine (a nonspecific vasodilator). Both tail-cuff
systolic blood pressure and mean arterial blood pressure were higher
in capsaicin-treated rats fed a high-salt diet and capsaicin treated
rats fed a high-salt diet plus prazosin when compared to capsaicin
treated-rats fed a high-salt diet plus losartan or hydralazine,
the vehicle-treated rats fed a high-salt diet, or capsaicin-treated
rats fed a normal salt diet. These results suggest that losartan
and hydralazine, but not prazosin, are able to prevent the development
of salt-induced hypertension in capsaicin-pretreated animals. Of
significance to understanding the pathophysiology of salt-sensitive
hypertension, these results revealed that there was an interaction
between the sensory nervous system and the RAAS in a manner that
prevents the development of salt-induced hypertension in sensory-intact
rats. This study also confirmed that capsaicin might impair the
natriuretic response to a high salt intake, as rats pretreated with
capsaicin and fed a high-salt diet have decreased urinary volume
and sodium excretion. Interestingly, losartan and hydralazine did
not protect against the impaired natriuretic response, even though
these agents did prevent the development of hypertension in salt-loaded
capsaicin pretreated rats. These results indicate that intact sensory
innervation is essential for the normal natriuretic response to
sodium loading and that the antihypertensive effects of losartan
and hydralazine may be mediated by mechanisms for example, vasodilatory
mechanism, other than those that protect against the impairment
of urinary sodium and water excretion in this model.
To further investigate the roles of the type 1 (AT1) and 2 (AT2)
angiotensin II (AII) receptors in the development of salt-induced
hypertension in capsaicin-pretreated rats,
we[54] treated capsaicin-pretreated rats fed a high-salt
diet with candesartan (a selective blocker of the AT1 receptor),
PD 123319 (a selective blocker of the AT2 receptor), or a combination
of these two drugs. Development of hypertension in capsaicin treated
rats fed a high-salt diet was prevented or attenuated by candesartan
and PD 123319, respectively, indicating that both of these
antagonists were protective and effective in lowering increased
blood pressure induced by a salt challenge in capsaicin-pretreated
animals. The antihypertensive effect of PD 123319 is unexpected
and the underlying mechanisms remain to be defined. Plasma renin
activity (PRA) was suppressed by high salt intake in both vehicle-
or capsaicin-treated rats, but it was significantly less suppressed
in the latter than in the former. This observation suggests that
PRA may be insufficiently suppressed in capsaicin-pretreated animals,
likely contributing to hypertension in these animals.
We next studied aldosterone and its interaction with
the sensory nervous system in the induction of salt-sensitive hypertension,
in light of the aforementioned finding that PRA is insufficiently
suppressed in neonatally capsaicin-pretreated rats challenged with
a salt load[54,55]. Both vehicle- and capsaicin-treated
rats fed a high-salt diet was given spironolactone, an aldosterone
receptor antagonist for 3 weeks. We found that chronic spironolactone
treatment appeared to restore renal functional impairment and prevented
the development of hypertension in neonatally capsaicin-pretreated
rats fed a high-salt diet[55]. This is in contrast to
our previous report with losartan and hydralazine, which have been
shown to attenuate elevated blood pressure in capsaicin pretreated
rats challenged with a salt load, but not able to improve renal
functional impairment[53]. These results indicate that
the antihypertensive effect of spironolactone in this model is mediated
by improving renal function, consistent with the role of aldosterone
receptors in the kidney that cause sodium and water retention.
Albeit markedly suppressed by salt loading, plasma aldosterone
levels (PAL) and PRA were significantly higher in capsaicin-pretreated
rats challenged with salt load than sensory-nerve-intact rats fed
the same high-salt diet[55]. This suggests PRA and PAL
are insufficiently suppressed in sensory-denervated rats, contributing
to increased salt sensitivity and renal functional impairment in
these animals. Insufficiently suppressed PAL in response to salt
loading can be attributed to one or both of the following: (i) increased
circulating and/or tissue AII levels; and/or (ii) upregulation of
the AII type I receptor in the zona glomerulosa of the adrenal gland,
a receptor to which binding of AII increases aldosterone synthesis
and secretion. We[55] found that the AT1 receptor content
in the adrenal gland was not altered in any of the experimental
groups, strongly suggesting that insufficiently suppressed PAL is
a reflection of insufficiently suppressed circulating and/or tissue
AII levels.
In contrast to above mentioned studies that define the role of
the RAAS in the development of hypertension in capsaicin treated
rats fed a high-salt diet, we studied the role of sensory nerves
in attenuating the development of hypertension induced by AII infusion[56].
AII or vehicle-infused rats were pretreated with capsaicin or vehicle.
Mean arterial pressure was higher in rats infused with AII, and
it was higher in AII-infused rats pretreated with capsaicin compared
to rats infused with AII alone. Northern blot analysis revealed
that AII-infused rats had an increase in the level of CGRP mRNA
in the dorsal root ganglia, suggesting that subpressor infusion
of AII either stimulates the synthesis of CGRP mRNA or retards its
degradation. Taken together, these data suggest that neuropeptides
released by sensory nerves attenuate elevated blood pressure induced
by AII infusion and that the increase in CGRP synthesis appears
to be a compensatory response to diminish increased blood pressure
induced by AII infusion. Furthermore, 24-h urinary and sodium excretions
were lower in AII-infused rats pretreated with capsaicin than they
were in rats infused with AII alone. These results are consistent
with the finding that degeneration of VR1 positive sensory nerves
impairs the natriuretic response to a salt load[52-55].
Role of the sympathetic nervous system Defining the
interaction between the sympathetic and sensory nervous systems,
we found that sympathectomy produced by administration of guanethidine
subcutaneously prevented the development of salt-sensitive hypertension
induced by sensory nerve degeneration[57]. This finding
suggests that: (i) enhanced sympathoexcitatory response occurs in
capsaicin-pretreated rats fed a high-salt diet, which may contribute
to increased salt sensitivity in these animals; and (ii) there is
a balance between antihypertensive effects of sensory nerves and
prohypertensive effects of the sympathetic nervous system in a normal
rat. This balance is disrupted following capsaicin-pretreatment
and consequential sensory nerve degeneration, such that the animal
is salt-sensitive. Sympathectomy may also result in less renin release
by withdrawing the stimulation of the ¦Á1-adrenergic receptors.
These findings appear to be in contrast to our previous results
in which prazosin is not able to prevent the development of salt-induced
hypertension in capsaicin-pretreated animals[53]. To
reconcile this finding about prazosin with the antihypertensive
effect of sympathectomy, one should keep in mind the following considerations:
(i) the dose of prazosin may not have been high enough to decrease
blood pressure in neonatally capsaicin-pretreated rats challenged
with a salt load, even though the same dose resulted in reduction
in blood pressure in spontaneously hypertensive rats[58];
(ii) alpha-1 adrenoreceptors are necessary for preventing salt-induced
hypertension, an idea supported by findings by Osborn et al[59]
who have shown that blockade of the ¦Á1-adrenoreceptor
with prazosin renders the rat salt-sensitive and leads to the development
of salt-sensitive hypertension; and (iii) the sympathetic nervous
system may contribute to the development of salt-induced hypertension
in neonatally capsaicin-pretreated rats via a non-¦Á1-adrenoreceptor
mecha-nism.
Role of the endothelin system We investigated the role of
endothelin-1 (ET-1) and its receptors in sensory-dependent salt-sensitive
hypertension, in light of the finding that AII is a stimulus for
ET-1 production[60-63]. We found that plasma ET-1 levels
and blood pressure were elevated in sensory-denervated rats fed
a high-salt diet. Moreover, development of salt-sensitive hypertension
in these rats can be prevented by blockade of the ETA receptor,
just as it can be prevented with losartan[53] and candesartan[54],
hydralazine[53], sympathectomy[57], and spironolactone[55].
Unlike chronic treatment with spironolactone[55], however,
blockade of the ETA receptor is not able to alleviate
renal functional impairment in capsaicin-pretreated rats fed a high-sodium
diet.
Furthermore, elevated plasma ET-1 levels may reflect one or both
of the following: (i) decreased internalization by ETB receptors,
which have been shown to act as clearance receptors for ET-1[64-65];
or (ii) increased production. Because we observed that plasma
ET-1 levels in sensory denervated rats that were salt loaded were
unaffected by blockade of the ETB clearance receptor[60],
it is clear that elevated plasma ET-1 levels are indeed the result
of increased production, consistent with the possibility of increased
synthesis and release of ET-1 secondary to insufficiently suppressed
PRA in these capsaicin-pretreated animals[54,55].
VR1-positive sensory nerves and pulmonary hypertension
The role of neuropeptides released by sensory nerves in hypoxic
pulmonary hypertension have been studied[66,67]. Tjen-A-Looi
revealed that rats pretreated with capsaicin and subsequently
placed in hypobaric hypoxia (10% O2, 16 d) had increased
pulmonary artery pressure and right ventricular hypertrophy compared
to sensory-nerve-intact rats subjected to the same hypoxia[66].
These investigators concluded that depleted stores of CGRP secondary
to capsaicin administration exacerbated hypoxic pulmonary hypertension.
Interestingly, these authors reported that depletion of SP did not
exacerbate pulmonary artery pressure and right ventricular hypertrophy.
Regarding the latter observation, it follows that endogenous CGRP
may indeed modulate pulmonary vascular tone and counterbalance hypoxic
pulmonary vasoconstriction, reducing elevated pulmonary artery pressure
and right ventricular hypertrophy in pulmonary hypertension.
In contrast to the protective effect of CGRP on pulmonary artery
pressure observed by Tjen-A-Looi[66], Zhou and Lai[67]
found that SP was implicated in pulmonary hyperten-sion. Zhou and
Lai induced ventilatory dysfunction and pulmonary hypertension in
Sprague-Dawley rats by administering monocrotaline (MCT). SP levels
were elevated 1-2 weeks after the administration of MCT. Compared
to rats given MCT alone, rats given MCT plus capsaicin showed attenuated
increases in pulmonary arterial pressure and the weight ratio of
right ventricle/(left ventricle+septum). These data suggest that
MCT produces pneumotoxicity that may be mediated or at least accompanied
by elevated SP levels. Because capsaicin treatment depletes this
neuropeptide, capsaicin attenuates MCT-induced pneumotoxicity[67].
Clinical and therapeutic implications
Given that excitation of VR1-positive sensory nerves is followed
by a refractory state, capsaicin has being found to have therapeutic
potential in the treatment of neuropathic pain[68]. But,
and as has been suggested within this review, capsaicin has implications
beyond the treatment of pain as an agent capable of acting on the
cardiovascular system. The observation that capsaicin (an agonist
of the VR1) is able to produce a hypotensive effect in SHR is an
indication that activation of the VR1 may be an efficacious means
of preventing the development of hypertension - a prospect with
far-reaching therapeutic implications[69].
Of growing interest is the compelling evidence that vanilloid receptors
on sensory nerves may mediate the vasodilator action of anandamide[70-74],
which was originally isolated from the brain as an endogenous cannabinoid
receptor ligand[75]. Indeed, our recent data indicate
that administration of methanandamide caused a greater hypotensive
effect in SHR rats as compared with control animals, suggesting
that anandamide may serve as an endogenous compound able to stimulate
VR1 and consequently produce a decrease in blood pressure[69].
It follows that changes in circulating or tissue anandamide levels
under particular pathophysiological conditions may alter VR1 function
and thereby regulate blood pressure. The search for endogenous VR1
activators and inhibitors is certainly motivated by the implications
that such vanilloid therapy may treat hyper-tension.
In addition to vanilloid therapy, there are broad implications
for the clinical application of neuropeptides stored in the endings
of VR1-positive sensory nerves. In particular, the clinical utility
of CGRP receptor agonists in the treatment of cardiovascular disorders
is discussed below and in greater detail in a review by Feuerstein
et al[76].
Considering its potent vasodilatory action, CGRP has been evaluated
in the treatment of subarachnoid hemorrhage and shown to relax severely
constricted vessels in animal models of this disorder[77].
However, the European CGRP in Subarachnoid Hemorrhage Study Group[78]
was not able to produce definitive evidence supporting the use of
this neuropeptide in the treatment of subarachnoid hemorrhage. Their
study was complicated by almost two-thirds of patients in the treatment
group not being able to complete the course of the trial because
of frequent episodes of CGRP-induced hypotension. Perhaps this adverse
systemic side effect could be minimized by intrathecal administration
of CGRP.
Other studies have shown that CGRP has potential beneficial hemodynamic
effects in congestive heart failure[79-80]. Shekhar et al
observed that CGRP infusion over 8 h increased cardiac output
by 72% while reducing right atrial and pulmonary wedge pressure[80].
Unfortunately, these favorable hemodynamic responses returned to
pre-infusion levels once CGRP delivery was withdrawn. The need for
continuous infusion of CGRP thus diminishes its clinical utility
in the treatment of congestive heart failure.
Similarly, CGRP has been evaluated in the treatment of coronary
heart disease. Indeed, it has been shown to improve exercise tolerance
in patients with chronic stable angina[81]. But, specificity
for CGRP or related agonists for the coronary vasculature has not
been demonstrated and CGRP infusion for the treatment of coronary
heart disease would thus be expected to produce systemic side effects,
as it does in the treatment of heart failure.
As another example of the possible clinical utility of CGRP, it
has been demonstrated that patients with Raynaud's disease are deficient
in cutaneous CGRP-containing nerve fibers[82]. However,
CGRP has not been shown to be useful in the treatment of this peripheral
vascular disease.
Conclusion remarks
It is estimated that 50 million individuals in the United
States suffer from hypertension. The detrimental consequences of
this disease involve myocardial infarction, congestive heart failure,
stroke, and renal failure. Despite intensive research in this field,
the molecular basis underlying human essential hypertension is largely
unknown and pharmacologic prevention of end organ damage induced
by hypertension is a challenge. Defining how sensory nerves sense
changes in the environment, alter their afferent and efferent activities,
and cross-talk with other systems to modulate cardiovascular and
renal function and blood pressure may provide valuable new insight
into the interactions that lead to hypertension and increased salt
sensitivity. Such insight may unveil novel pharmacologic approaches
to tackle hypertension and end organ damage. The study of abnormalities
in VR1 expression, VR1-induced release of sensory neurotrans-mitters,
and post-signaling pathways may also have significant impact in
our understanding of the pathogenesis of hypertension and have far-reaching
clinical and therapeutic implications.
Acknowledgement
Dr Wang is an American Heart Association Established Investigator
and she would like to express her gratitude to all the research
fellows, students, and visiting scientists who have participated
and contributed to the aforementioned studies.
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