See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/255966144

Role of central and peripheral chemoreceptors in

vasopressin secretion control.
ARTICLE in ENDOCRINE METABOLIC & IMMUNE DISORDERS - DRUG TARGETS(FORMERLY CURRENT DRUG TARGETS IMMUNE ENDOCRINE & METABOLIC DISORDERS) SEPTEMBER 2013

CITATION

READS

209

7 AUTHORS, INCLUDING:
Michele Iovino

Giorgio Fiore

Azienda Sanitaria Locale Salerno

Universit degli Studi di Bari Aldo Moro

101 PUBLICATIONS 627 CITATIONS

6 PUBLICATIONS 37 CITATIONS

SEE PROFILE

SEE PROFILE

Vincenzo Triggiani
Universit degli Studi di Bari Aldo Moro
69 PUBLICATIONS 562 CITATIONS
SEE PROFILE

All in-text references underlined in blue are linked to publications on ResearchGate,

letting you access and read them immediately.

Available from: Michele Iovino

Retrieved on: 01 April 2016

Send Orders for Reprints to reprints@benthamscience.net

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, 13, 000-000

Role of Central and Peripheral Chemoreceptors in Vasopressin Secretion

Control
Michele Iovino*, Edoardo Guastamacchia, Vito Angelo Giagulli, Giorgio Fiore, Brunella Licchelli,
Emanuela Iovino and Vincenzo Triggiani
Interdisciplinary Department of Medicine-Endocrinology and Metabolic Diseases. University of Bari Aldo Moro,
Bari, Italy
Abstract: In this review, we analyzed the role played by central and peripheral chemoreceptors (CHRs) in vasopressin
(AVP) secretion control. Central neural pathways subserving osmotic and non-osmotic control of AVP secretion are
strictly correlated to brain areas participating in chemoreception mechanisms. Among the different brain areas involved in
central chemoreception, the most important site has been localized in the retrotrapezoid nucleus of the rostral ventrolateral
medulla. These central CHRs are able to detect very small pH/CO2 fluctuations, participating in brain blood flow
regulation, acid-base balance and blood pressure control. Decreases in arterial pH and increases in arterial pCO2 stimulate
AVP release by the Supraoptic and Paraventricular Nuclei. Carotid CHRs transduce low arterial O2 tension into increased
action potential activity, leading to bradycardia and coronary vasodilatation via vagal stimulation, and systemic
vasoconstriction via catecholaminergic stimulation. Stimulation of carotid CHRs by hypoxia increases neurohypophyseal
blood flow and AVP release, an effect inhibited by CHRs denervation. Two renal CHRs have been identified: Type R1
CHRs do not have a resting discharge but are activated by renal ischemia and hypotension; Type R2 CHRs have a resting
discharge and respond to backflow of urine into the renal pelvis. Signals arising from renal CHRs modulate the activity of
hypothalamic AVPergic neurons: activation of R1 and R2 CHRs, following increased intrapelvic pressure with solutions
of mannitol, NaCl and KCl, produces a significant increase of AVP secretion and the same effect has been obtained by the
intrarenal infusion of bradykinin, which excites afferent renal nerves, as well as by the electrical stimulation of these
nerves.

Keywords: Vasopressin, chemoreceptors, hypoxia, ventilatory drive.

INTRODUCTION
The circulating peptide vasopressin (AVP), is synthesized
from hypothalamic magnocellular neurons of supraoptic
(SON) and paraventricular nuclei (PVN), and transported to
posterior pituitary where AVP is released into the peripheral
circulation in response to increased plasma osmolality or to
hypovolemia.
Previously, we have analyzed the role played by
osmoreceptors and baroreceptors in the control of AVP
release, and the central pathways and the neurotransmitters
involved in this control [1]. In this review, we analyzed the
role of central and peripheral chemoreceptors (CHRs) in
AVP secretion control (Fig. 1).
CENTRAL CHEMORECEPTORS
Central chemoreception has been localized in the rostral
ventrolateral medulla (RVLM), even if several brain areas
participate in chemoreception mechanisms: nucleus tractus
solitarius (NTS), locus coeruleus (A6), brainstem raphe
nuclei (B7-B8-B9), pre-Btzinger complex, fastigial nucleus
*Address correspondence to this author at the Interdisciplinary Department of
Medicine-Endocrinology and Metabolic Diseases. University of Bari Aldo
Moro, Bari, Italy; Tel: 0039 0828362269;
E-mail: micheleiovino06@libero.it
1871-5303/13 $58.00+.00

(FN) and hypothalamus [2,3]. However, there is evidence

that medullary neurons of the retrotrapezoid nucleus (RTN)
of the RVLM represent the most important site of
chemoreception [4], indeed they are a specialized population
of Central Nervous System (CNS) cells able to detect very
small pH/CO2 fluctuations.
Central chemoreceptors participate in the regulation of
alveolar ventilation, brain blood flow and metabolism, acidbase balance and blood pressure via the sympathetic tone,
contributing to the maintenance of the appropriate pH for
optimal protein structure and function [5]. The mechanisms
involved in RTN chemoreception are H+ -mediated activation
of pH-sensitive neurons and the regulation of blood flow. In
fact, changes in cerebral blood flow affect the chemoreflex
[6]: reduction of blood flow by vasoconstriction acidifies
tissue pH and increases the ventilatory response to CO2;
inversely vasodilatation increases tissue pH and decreases
the chemoreceptor activation. Acidification of the RTN
increase pH-sensitive neurons and blood flow. These data
might indicate that RTN play a tonic excitatory role in the
central network regulating breathe during sleep; however,
during wakefulness, the chemoreceptor area, as the RTN,
receives excitatory input from many regions such as the
hypothalamus and the brainstem raphe nuclei [3,4].
CO2/H+ -sensitive RTN neurons have extensive dendrites
within the marginal layer of the ventral medullary surface
2013 Bentham Science Publishers

2 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3

Iovino et al.

Fig. (1). Midsaggital Section of rat brain illustrating central neural areas by which chemoreceptor inputs from carotid, aortic and renal sites
may be carried to hypothalamic neurons of SON and PVN. IX: glossopharyngeal nerve; X: vagus nerve; NTS: nucleus tractus solitarius;
RTN: retrotrapezoid nucleus; CVLM: caudal ventrolateral medulla; FN: fastigial nucleus; A6: locus coeruleus: B7-B8-B9: raphe 5-HTergic
neurons.

and are glutaminergic [7]. They project to pontomedullary

respiratory centers and express the transcription factor
PHOX2B. Mutations in the gene that encodes PHOX2B cause
a respiratory deficit named congenital central hypoventilation
syndrome (CCHS) [8] the principal symptom of which is the
hypoventilation during the sleep. Transgenic animal model
of CCHS shows reduced ventilatory response to CO2 and a
significant reduction in the number of RTN neurons [8]. The
presence of PHOX2B in RTN neurons supports the
possibility that these neurons play an important role as
chemoreceptors. Abbot and coworkers, using a lentovirus to
target expression of the light-activated cationic channel
rhodopsin in PHOX2B-expressing neurons, observed that
photo-stimulation caused a marked increase in phrenic nerve
activity [9].
In addition to CO2/H+ fluctuations, RTN neurons are
modulated by various neurotransmitters. They receive
synaptic inputs from brainstem serotoninergic (5-HTergic)
raphe neurons and locus coeruleus noradrenergic (NAergic)
neurons increasing the activity of RTN neurons and their
CO2/H+ sensitivity [2,3,10]. Similarly, ATP released by
astrocytes plays an important role in mechanisms regulating
central chemoreception [11,12]. Indeed, hypercapnia causes
release of ATP within the RTN [12], as well as administration
of ATP into the RTN stimulates the respiratory drive. These
effects were prevented by the ATP receptor antagonist
PPADS [12]. It has been observed that PPADS decreases
phrenic nerve recordings of respiratory activity in rats [13].
Therefore, it is reasonable to suppose that purinergic P2Xreceptors mediate the effects of ATP on RTN neurons [11].
A strong relationship exists between the mechanisms
regulating the chemoreception and blood flow. Indeed,
changes in CO2/H+ act also as a potent vasodilator [6].
CO2/H+ -mediated vasodilatation increases blood flow

inducing a removal of metabolically produced CO2 .

Astrocytes regulate blood flow in response to neural activity
[14], contribute to CO2/H+ -mediated vasodilatation [15], and
release ATP [16] which stimulates arteriolar dilation by
activation of P2Y receptors [17].
CAROTID CHEMORECEPTORS
Carotid body chemoreceptors play a role of sensing O2,
pH, CO2, osmolality and temperature. They are located on
the external carotid arteries near carotids bifurcation. They
are, also, located in the aortic body and aortic arch. Afferent
nerve fibers from carotid bodies join with the sinus nerve
before entering the glossopharyngeal nerve. They transduce
low arterial O2 tension into increased action potential activity
on the carotid sinus nerves, which contributes to resting
ventilatory drive, increased ventilatory drive in response to
hypoxia, arousal responses to hypoxia during sleep, upper
airway muscle activity, blood pressure control and
sympathetic tone [18]. Therefore, chemoreceptor activation
causes bradycardia and coronary vasodilatation via
vagal stimulation, and systemic vasoconstriction via
catecholaminergic stimulation. Chemoreceptors respond to
hypoxia with an increase in intracellular calcium and
secretion of multiple neurotransmitters. Translation of this
secretion into action potential is induced by the excitability
of the afferent nerve terminals that is produced by the
voltage-dependence of activation of Na+ channels that are
present at the soma of chemoreceptor afferent neurons [19].
RENAL CHEMORECEPTORS
Two types of renal chemoreceptors have been identified:
R1 and R2 chemoreceptors. Their stimulation give origin to
supraspinal and spinal-mediated autonomic reflexes. Electro-

Role of Central and Peripheral Chemoreceptors in Vasopressin

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3

physiological studies showed that R1 chemoreceptors do not

have a resting discharge but are activated after complete
renal ischemia (occlusion of the renal artery), prolonged
occlusion of the renal vein and hypotension following
asphyxia or hemorrhage. Their activation ceases after reentry of blood into the kidney.
R2 chemoreceptors have a resting discharge and respond
significantly to backflow of normal urine into the renal
pelvis. The resting discharge rate of these R2 chemoreceptors
is increased after backflow of urine and declines after
diuresis provoked by extracellular volume expansion [20].
Therefore, R1 and R2 chemoreceptors are two types of
afferent sensory units which are sensitive to the chemical
environment of renal interstitium [21-23].
AFFERENT PATHWAYS FROM CENTRAL AND
CAROTID CHEMORECEPTORS TO HYPOTHALAMIC
AVPERGIC NEURONS OF THE SUPRAOPTIC AND
PARAVENTRICULAR NUCLEI
There is evidence that the activation of carotid chemoreceptors, induced following bilateral carotid occlusion,
stimulates AVP release. This response is blocked by lesions
of the septal area, and the region medial and rostral to the
SON and PVN as the medial preoptic area and anterior
hypothalamus, but not by lesions in caudal regions of the
hypothalamus [24]. Therefore, it has been proposed that
afferent pathways, originating from carotid body chemoreceptors, to hypothalamic AVPergic neurons pass in the
lateral hypothalamus to the septal area, where they turn
medially and descend through the medial part of the rostral
hypothalamus. The role of the septal forebrain has been
analyzed in our previous review [1]. Therefore, septal nuclei
play a pivotal role either in osmoreceptor- and baroreceptormediated AVP release [25-28] but also in chemoreceptors
dependent control of AVP secretion [24].
Afferent impulses from carotid chemoreceptors are
convoyed in the vagi and carotid sinus nerves to the nucleus
tractus solitarius (NTS) of the dorsal medulla oblongata.
Afferent impulses from chemoreceptors stimulate an
excitatory response and those from baroreceptors an
inhibitory response by AVPergic neurons in the SON and
PVN, by means of different projections from the NTS to
these nuclei [29].
The excitatory projection, that is stimulated by
chemoreceptors and originates in the NTS, is a neural
pathway that involves the A1 NAergic cell group. Indeed,
microinjection of the presynaptic alpha2-adrenergic agonist
clonidine into the NTS blocked AVP release induced by
hypovolemia and this effect was prevented by the alpha2adrenoceptor blocker yohimbine, indicating that NAergic
receptors were required for the biological response [30]. In
addition, electrical simulation of the NTS and A1 NAergic
afferents enhances the activity of AVPergic neurons of SON
and PVN [31,32] and the release of AVP also following
transection of the vagi and spinal cord [33]. Bilateral
electrolytic lesions of the A1 NAergic cell group abolished
the effects of NTS stimulation on AVPergic neurons and
injections of GABA into A1 NAergic neurons blocked the
AVP release induced by NTS stimulation [34]. A high

proportion of A1 and A6 NAergic neurons receive peripheral

chemoreceptor inputs thus showing that A1 and A6 area
neurons projecting to SON is part of central circuitry
subserving AVP secretion where chemoreceptor stimulation
play an important role [35].
It has been also proposed that information arising from
carotid chemoreceptors after histotoxic-anoxia stimulation
mediates the role played by AVP in the NTS in glucose
homeostasis. In fact AVP infusion into the NTS increased
significantly arterial glucose and decreased brain arterial
venous glucose, an effect that was blocked by the
administration of an AVP antagonist [36].
It has been observed that rostral ventrolateral medulla
(RVLM) is involved in the mediation of cardiovascular
responses to peripheral chemoreceptor stimulation involving
heart rate and blood pressure. Neurons in this area respond to
excitatory amino acid and AVP inputs following chemoreceptor stimulation. Indeed, the amino acid antagonist
kynurenate microinjected into RVLM inhibited the pressure
response to chemoreceptor stimulation. The same inhibitory
response on blood pressure has been obtained after
intravenous injection of a AVP antagonist [37]. These data
show that carotid body chemoreceptor activation mediate the
pressure response via NMDA receptors in the RVLM and
stimulate AVP release [38].
Raphe nuclei of the brainstem represent another site
involved in central chemoreception playing a synergistic role
with RTN neurons via a 5-HTergic neurotransmission [10].
Indeed, axons arising from 5-HTergic raphe neurons synapse
in the RTN and 5-HT increases the activity of RTN
chemoreceptors [10] and some data indicate a stimulatory
role of raphe 5-HTergic neurons on AVP release [39-42].
Also the FN of the cerebellum, a brain region participating in
chemoreception and in cardiovascular responses, modulates
AVP release. Indeed, electrical stimulation of the FN
increases AVP release [43], whereas the electrolytic lesion
inhibits it [44]. These neural pathways use a variety of
neurotransmitters, and the different neurotransmitters
interact with each other in determining hormone release.
Sladek and coworkers showed that simultaneous exposure to
ATP, a neurotransmitter agonist of purinergic receptors, and
phenylephrine (PE), an agonist of alpha1-adrenergic
receptors, induces a very high release of AVP that is
expressed by an increase in the peak response and in a
response that is sustained for hours. The mechanisms
subserving this response are: the activation of P2X and P2Y
purinergic receptors, activation of protein kinase C, gene
transcription ad sustained increase of Ca++ [45-48].
Stimulation of carotid and aortic chemoreceptors by
hypoxia increases neurohypophyseal blood flow and AVP
release, an effect completely inhibited after chemoreceptor
denervation [49]. Therefore, the AVP release appears to
be mediated via these chemoreceptors, probably by altering
the afferent pathway from carotid chemoreceptors to
hypothalamic AVPergic neurons [50]. Chemoreceptors
mediate AVP release following decreases in arterial pH and
increases in arterial pCO2 [51,52].
Almitrine bismesylate, an agonist of peripheral
chemoreceptors located on the carotid bodies, that increases

4 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3

arterial O2 tension and decreases arterial CO2 tension,

produces diuresis and natriuresis. This response is abolished
by glossopharyngeal nerve section indicating that this effect
may be mediated via carotid chemoreceptors [53]. The
release of AVP after exposure to a hot environment may also
be due to stimulation of the chemoreceptor mechanism. The
peripheral vasodilatation induced by warm with a decrease in
central blood volume could stimulate the receptors. Exposure
of normal subjects for two hours at 50C increases plasma
AVP concentration from four to fivefold [54].
AFFERENT PATHAWAYS FROM RENAL CHEMORECEPTORS TO HYPOTHALAMIC AVPERGIC
NEURONS OF SON AND PVN
Electrical stimulation of renal nerves increases AVP
release. It has been shown that activation of R1 and R2
chemoreceptors, following increased intrapelvic pressure
with solutions of mannitol, NaCl or KCl, produces a
significant increase of AVP secretion [55-57]. In addition,
intrarenal infusion of bradykinin, which is known to excite
afferent renal nerves, increases the activity of AVPergic
neurons in the SON of rats and increases AVP release in
rabbits. These responses are significantly inhibited following
renal denervation showing that the kidneys can influence the
secretion of AVP via the afferent renal nerves [58].
A relationship between the activity of afferent renal
nerves and R2 chemoreceptors has been observed. In fact,
intrapelvic pressure increases, with non-diuretic urine or by
intrapelvic backflow of diuretic urine, and stimulate the
activity both afferent renal nerves and R2 chemoreceptors.
Electrophysiological data indicate similar responses between
afferent renal nerve activity and R2 chemoreceptors during
intrapelvic pressure increases. Therefore, it has been
supposed that the activation of afferent renal nerve activity is
induced from R2 chemoreceptors inputs [59].
Renal chemoreceptors evoke renorenal reflexes via renal
afferent fibers. Evidence indicate that renal afferent fibers
may also regulate secretion of AVP. They enter the spinal
cord and transport renal information to the brain. Neurons in
the L2-T11 segments of cat spinal cord with excitatory
response to renal A,
and C fiber inputs project to the
medial medullary reticular formation and to the caudal and
rostral ventrolateral medulla [60] where are located NTS
neurons that are involved in the control of AVP secretion
[30,31,33,61-63].
Electrical stimulation of renal afferent nerves increases
the activity of AVPergic neurons of the PVN [64], thus
showing that sensory information arising from renal
chemoreceptors modulate the activity of hypothalamic
AVPergic neurons.

of these receptors. On the other hand, hypovolemia and

hypotension, that elicit AVP release, inhibit the baroreceptor
afferent activity. Signals from these baroreceptors are carried
to the central nervous system via the glossopharyngeal
(IXth) and vagus (Xth) cranial nerves, which project to, and
synapse in the NTS [66]. Under resting conditions,
baroreceptors are tonically active exerting an inhibitory role
on AVP release [62,67-71]. In fact, lesions of the NTS
elevate plasma AVP levels, thus showing that the ablation of
the NTS removing this inhibition inducing AVP release [62].
However, the IXth and Xth nerves also carry chemoreceptor
afferents that act to stimulate AVP release [65,68], therefore
baroreceptor afferents projecting to the NTS act tonically to
inhibit AVP release, whereas stimulation of peripheral
chemoreceptors, which project to the NTS, stimulate the
release of AVP.
Central chemoreceptors play a role on blood pressure via
the sympathetic tone [5] and ATP, released from neural
pathways, stimulates vasodilatation by activation of P2X and
P2Y purinergic receptors [17]. Therefore, as Sladek's data
indicate, the P2X subtypes play an important role in the
response of AVP to simultaneous exposure to ATP+PE. The
subtypes of P2X receptors differ in their rate of desensitation
thus showing the difference in the response to ATP+PE
concerning the abrupt release of AVP to orthostatic
hypothension versus sustained responses to chronic
hypovolemia or vasodilatation [47].
Finally, it is interesting to underline that the central
neural pathways subserving osmotic and non-osmotic control
of AVP secretion are correlated to brain areas participating
to chemoreception mechanisms.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1]

[2]

[3]
[4]

CONCLUSIONS
In addition to osmoreceptor- and baroreceptor-control of
AVP synthesis, transport and release, chemoreceptors play
an important role in the control of AVP secretion. There is
evidence that baroreceptors located in the atria of the heart
are low pressure receptors, whereas baroreceptors located in
the aortic arch and carotid sinus are high pressure receptors
[65]. Therefore, increases in pressure stimulate the activity

Iovino et al.

[5]
[6]

[7]

Iovino, M.; Guastamacchia, E.; Giagulli, V.A.; Licchelli, B. and

Triggiani, V. (2012) Vasopressin Secretion Control: Central Neural
Pathways, Neurotransmitters and Effects of Drugs. Curr. Pharma.
Des. 18, 4714-4724.
Feldman, I.L.; Mitchell, G.S. and Nattie, F. (2003) Breating:
rhytmicity, plasticity, chemosensivity. Ann. Rev. Neurosci. 26, 239266.
Guyenet, P.G. (2008) The 2008 Carl Ludwig Lecture: retrotrapezoid
nucleus, CO2, homeostasis and breathing automaticity. J Appl.
Physiol. 105(2), 404-16.
Guyenet, P.G.; Bayliss, D.A.; Stornetta, B.L.; Fortuna, M.G.;
Abbott, S.B. and De Puy, S.D. (2009) Retrotrapezoid nucleus:
respiratory, chemosensitivity and breating automaticity. Respir.
Physiol. Neurobiol. 168(1-2), 59-68.
Nattie, E. and Li, A. (2012) Central chemoreceptors: Locations and
Functions. Compr. Physiol. 2, 221-254.
Ainslie, P.N. and Duffin, J. (2009) Integration of cerebrovascular
CO2 reactivity and chemoreflex control of breating: mechanisms of
regulation, measurement and interpretation. Am. J. Physiol. Regul.
Integr. Comp. Physiol. 296 (5): R1473-R1495.
Mulkey, D.K., Stornetta, B.L.; Weston, M.C., Simmons, J.R.,
Parker, A.; Bayliss, D.A. and Guyenet, P.G. (2004) Respiratory

Role of Central and Peripheral Chemoreceptors in Vasopressin

[8]

[9]

[10]

[11]

[12]

[13]

[14]
[15]

[16]
[17]

[18]
[19]
[20]

[21]
[22]
[23]
[24]

[25]
[26]

[27]

[28]

[29]
[30]

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3

control by ventral surface chemoreceptor neurons in rats. Nat.

Neurosci. 7(12), 1360-1369.
Dubreuil, V.; Ramanantsoa, N.; Trocher, D.; Vaubourg, V.; Amiel,
I.; Gallego, J.; Brunet, J.F. and Goridis, C. (2008) A human
mutation in PHOX2B causes lack of CO2 chemosensitivity fatal
central apnea and specific loss of parafacial neurons. Proc. Natl.
Acad. Sci. UASA 105(3), 1067-1072.
Abbott, S.B.; Stornetta, B.L.; Fortuna, M.G.; DePuy, S.D.; West,
C.H.; Harris, T.E. and Guyenet, P.G. (2009) Photostimulation of
retrotrapezoid nucleus phox2b-expression neurons in vivo produces
long-lasting activation of breathing in rats. J. Neurosci. 29(18),
5806-5819.
Mulkey, D.K.; Rosin, D.J.; West, G.; Takakura, A.C.; Moreira,
T.S.; Bayliss, D.A. and Guyent, P.G. (2007) Serotonergic neurons
activate chemosensitive retrotrapezoid nucleus neurons by a phindependent mechanism. J. Neurosci. 27(51), 14128-14138.
Gourine, A.V.; Atkinson, J.; Deuchars, J. and Soyer, K.M. (2003)
Purinergic signalling in the medullary mechanisms of respiratory
control in the rat: respiratory neurons express the P2X2 receptor
subunit. J. Physiol. 552(Pt1), 197-211.
Gourine, A.V.; Laudet, F.; Dale, N. and Snyer, K.M. (2005) ATP is
a mediator of chemosensory transduction in the central nervous
system. Nature 436(7047), 108-111.
Wenker, I.C.; Sobrinho, C.R.; Takakura, A.C.; Moreira, T.S. and
Mulkey, D.K. (2012) Regulation of ventral surface CO2/H+sensitive neurons by purinergic signalling. J. Physiol. 590(Pt9),
2137-2150.
Hayden, P.G. and Carmignato, G. (2006) Astrocyte control of
synaptic transmission and neurovascular coupling. Physiol. Rev.
86(3), 1009-1031.
Xu, H.I. and Pellegrino, D.A. (2007) ATP release and hydrolysis
contribute to rat pial arteriolar dilatation elicited by neuronal
activation. Exp. Physiol. 92(4), 647-651.
Guthrie, P.B.; Knannenherger, L.; Segal, M.; Bennett, M.V.;
Charles, A.C. and Kater, S.B. (1999) ATP released from astrocytes
mediates glial calcium waves. J. Neurosci. 19(2), 520-528.
Horiuchi, T.; Dietrich, H.H.; Hongo, K. and Darey, R.G. (2003)
Comparison of P2 receptor subtypes producing dilation in rat
intracerebral arterioles. Stroke. 34(6), 1473-1478.
Carroll, J.L. and Kim, I. (2013) Carotid chemoreceptor resetting
revisited. Respir. Physiol. Neurobiol. 185(1), 30-43.
Donnelly, D.F. (2013) Voltage-gated NA+ channels in chemoreceptor
afferent neurons. Potential roles and changes with development.
Respir Physiol Neurobiol. 185(1), 67-74.
Wu, M.S.; Chien, C.T. and Chen, C.F. (1997) Renal R2
chemoreceptor activity is attenuated after back heating in the rat.
Neurosci. Lett. 229(2), 101-104.
Recordati, G.; Moss, N.G.; Genovesi, S. and Rogenes, P. (1981)
Renal chemoreceptors. J. Auton. Nerv. Syst. 3(2-4), 237-251.
Recordati, G.; Genovesi, S. and Cerati D (1982) Renorenal reflexes
in the rat elicited upon stimulation of renal chemoreceptors. J.
Auton. Nerv. Syst. 6(2), 127-142.
Recordati, G. (1986) Chemoreceptors in the kidney. Physiology. 1,
65-66.
Harris, M.C.; Ferguson, A.V. and Banks, D. (1984) The afferent
pathway for carotid body chemoreceptor input to the hypothalamic
supraoptic nucleus in the rat. Pflugers Arch. 400(1), 80-87.
Iovino, M.; Poenaru, S. and Annunziato, L. (1983) Basal and thirstevoked vasopressin secretion in rats with electrolytic lesion of the
medio-ventral septal area. Brain Res. 258(1), 123-126.
Iovino, M. and Steardo, L. (1985) Effects of septal lesions on the
response of vasopressin to angiotensin II. Ann. Endocrinol. 46(2),
113-117.
Iovino, M. and Steardo, L. (1986) The role of the septal area in the
regulation of drinking behaviour and plasma ADH secretion. In: De
Caro, G.; Epstein, A.N. and Massi, M. The Physiology of Thirst
and Sodium Appetite. Plenum Press, New York 1986, pp. 367-374.
Iovino, M.; Papa, M.; Monteleone, P. and Steardo, L. (1989)
Changes in magnocellular neurosecretory activity following
septal forebrain lesions: morphological and biochemical data.
Neuroendocrinol. Lett. 11, 361-369.
Bisset, G.W. and Chowdrey, H.S. (1988) Control of release of
vasopressin by neuroendocrine reflexes. Q.J. Exp. Physiol. 73(6),
811-872.
Iovino, M.; Vanacore, A. and Steardo, L. (1990) Alpha2-adrenergic
stimulation within the nucleus tractus solitarius attenuates

[31]

[32]
[33]

[34]
[35]

[36]

[37]

[38]
[39]

[40]
[41]

[42]
[43]

[44]
[45]

[46]
[47]

[48]

[49]
[50]

[51]

[52]
[53]

vasopressin release induced by depletion of cardiovascular volume.

Pharmacol. Biochem. Behav. 37(4), 821-824.
Day, T.A. and Renaud, L.P. (1984) Electrophysiological evidence
that noradrenergic afferents selectively facilitate the activity of
supraoptic vasopressin neurons. Brain Res. 303(2), 233-240.
Day, T.A. (1989) Control of neurosecretory vasopressin cells by
noradrenergic projections of the caudal ventrolateral medulla.
Prog. Brain Res. 81, 303-317.
Yamane, Y.; Nakai, M.; Yamamoto, J.; Umeda, Y. and Ogino, K.
(1984) Release of vasopressin by electrical stimulation of the
intermediate portion of the nucleus of the tractus solitarius in rats
with cervical spinal cordotomy and vagotomy. Brain Res. 324(2),
358-360.
Day, T.A. and Sibbald, J.R. (1989) A1 cell group mediates solitary
nucleus excitation of supraoptic vasopressin cells. Am. J. Physiol.
257(5 Pt 2), R1020-1026.
Li, Y.W.; Gieroba, Z.J. and Blessing, W.W. (1992) Chemoreceptor
responses of A1 area neurons projecting to supraoptic nucleus. Am.
J. Physiol. 263 (2 Pt 2), R310-307.
Montero, S.A.; Yarkov, A.; Lemus, M.; Alvarez-Buylla, E.R. and
Alvarez-Buylla, R. (2006) Carotid chemoreceptor reflex
modulation by arginine-vasopressin microinjected into the nucleus
tractus solitarius in rats. Arch. Med. Res. 37(6), 709-716.
Amano, M.; Asari, T. and Kubo, T. (1994) Excitatory amino acid
receptors in the rostral ventrolateral medulla mediate hypertension
induced by carotid body chemoreceptor stimulation. Naunyn
Schmiedebergs Arch Pharmacol. 349(6), 549-54.
Sapru, H.N. (1996) Carotid chemoreflex. Neural pathways and
transmitters. Adv. Exp. Med. Biol. 410, 357-364.
Tangapregassom, A.M.; Tangapregassom, M.J. and Soulairac, A.
(1974) Effets des lesions de la region du raphe mesencephalique
sur le comportement de soif et la neurosecretion hypothalamique
anterieure du rat. Ann. Endocrinol. 35(6), 667-668.
Iovino, M. and Steardo, L. (1985) Effect of substances influencing
brain serotonergic transmission on plasma vasopressin levels in the
rat. Eur. J. Pharmacol 113(1), 99-103.
Pergola, P.E.; Sved, A.F.; Voogt, J.L. and Alper, R.H. (1993)
Effect of serotonin on vasopressin release: a comparison to
corticosterone, prolactin and renin. Neuroendocrinology. 57(3),
550-558.
Jorgensen, H.S. (2007) Studies on the neuroendocrine role of
serotonin. Dan. Med. Bull. 54(4), 266-288.
Del Bo, A.; Sved, A.F. and Reis, D.J. (1983) Fastigial stimulation
releases vasopressin in amounts that elevate arterial pressure. Am.
J. Physiol. 244(5), H687-H694.
Sved, A.F.; Scott, P.J. and Kole, M. (1985) Cerebellar lesions
attenuate vasopressin release in response to hemorrhage. Neurosci.
Lett. 55(1), 65-70.
Kapoor, J.R. and Sladek, C.D. (2000) Purinergic and adrenergic
agonists synergize in stimulating vasopressin and oxytocin release.
J. Neurosci. 20(23), 8868-75.
Sladek, C.D. and Kapoor, J.R. (2001) Neurotransmitter/neuropeptide
interactions in the regulation of neurohypophyseal hormone
release. Exp. Neurol. 171(2), 200-9.
Sladek, C.D. and Song, Z. (2008) Regulation of vasopressin release
by coreleased neurotransmitters: mechanisms of purinergic and
adrenergic synergism. Prog. Brain. Res. 170, 93-107.
Song, Z. and Sladek, C.D. (2006) Site of ATP and phenylephrine
synergistic stimulation of vasopressin release from the hypothalamoneurohypophyseal system. J. Neuroendocrinol. 18(4),
266-72.
Wilson, D.A.; Hanley, D.F.; Feldman, M.A. and Traystman. R.J.
(1987) Influence of chemoreceptors on neurohypophyseal blood
flow during hypoxic hypoxia. Circ. Res. 61(5 Pt 2), II94-101.
Hanley, D.F.; Wilson, D.A.; Feldman, M.A. and Traystman, R.J.
(1988) Peripheral chemoreceptor control of neurohypophyseal
blood flow. Am J Physiol. 254(4 Pt 2), H742-50.
Wood, C.E.; Chen, H.G. and Bell, M.E. (1989) Role of vagosympathetic fibers in the control of adrenocorticotropic hormone
vasopressin and rennin responses to hemorrhage in fetal sheep.
Circ. Res. 64(3), 515-523.
Wood, C.E. and Chen, H.G. (1989) Acidemia stimulates ACTH,
vasopressin and heart rate responses in fetal sheep. Am. J. Physiol.
257(2 Pt 2), R344-R349.
Bradsley, P.A.; Johnson, B.F.; Stewart, A.G. and Barer, G.R.
(1991) Natriuresis secondary to carotid chemoreceptor stimulation

6 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3

[54]
[55]
[56]

[57]

[58]
[59]

[60]
[61]

[62]

with almitrine bismesylate in the rat: the effect on kidney function

and the response to renal denervation and deficiency of antidiuretic
hormone. Biomed. Biochem. Acta 50(2), 175-182.
Segar, W.E. and Moore, W.W. (1968) The regulation of antidiuretic
hormone release in man. J. Clin. Invest. 47(9), 2143-2151.
Yamamoto, A.; Keil, L.C. and Reid, I.A. (1991) Activation of renal
mechanoreceptors increases vasopressin release in rabbits. Am. J.
Physiol. 261(2 Pt 2), R484-R490.
Golin, R.; Keil, L.C.; Chou, L. and Reid, I.A. (1993) Activation of
renal R1 chemoreceptors increases vasopressin concentration in
rabbits. J. Hypertens. Suppl. 11(5), S182-S183.
Shiotsu, T.; Yamamoto, A.; Kagawa, S.; Tamaki, T.; Abe, Y. and
Reid, I.A. (1995) Effect of moderately increased intrapelvic
pressure on renal tissue pressure and vasopressin release in rabbits.
Hypertens. Res. 18(3), 197-202.
Reid, I.A.; Yamamoto, A.; Keil, L.C. and Chou, L. (1991) Role of
afferent renal nerves in the control of vasopressin secretion. Clin. J.
Physiol. 34(1), 93-104.
Moss, N.G. and Karastojanova, I.V. (1997) Static and dynamic
responses of renal chemoreceptor neurons to intrapelvic pressure
increases in the rat. J. Auton. Nerv. Syst. 63(3), 107-114.
Ammons, W.S. (1992) Bowditch Lecture. Renal afferent inputs to
ascending spinal pathways. Am. J. Physiol. 262 (2 Pt 2), R165R176.
Raby, W.N. and Renaud, L.P. (1989) Dorsomedial medulla
stimulation activates rat supraoptic oxytocin and vasopressin
neurones through different pathways. J. Physiol. 417, 279-294.
Sved, A.F.; Imaizumi, T.; Talman, W.T. and Reis, D.J. (1985)
Vasopressin contributes to hypertension caused by nucleus tractus
solitarius lesions. Hypertension. 7(2), 262-267.

Received: 24 March, 2011

Accepted: 29 March, 2012

[63]

[64]
[65]

[66]

[67]
[68]

[69]
[70]

[71]

Iovino et al.
Sawchenko, P.E. and Swanson, L.W. (1982) The organization of
noradrenergic pathways from the brainstem to the paraventricular
and supraoptic nuclei in the rat. Brain Res. 257(3), 275-325.
Ciriello, J. (1998) Afferent renal inputs to paraventricular nucleus
vasopressin and oxytocin neurosecretory neurons. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 275(6 Pt 2), R1745-R1754.
Share, L. and Levy, M.N. (1966) Effect of carotid chemoreceptor
stimulation on plasma antidiuretic hormone. Am. J. Physiol. 210,
157-161.
Kalia, M.P. (1981) Localization of aortic and carotid baroreceptor
and chemoreceptor primary afferents in the brain stem. In: Buckely,
J.P. and Ferrario, C.M. Central Nervous System Mechanisms in
Hypertension. Raven press. New York 1981: pp. 9-24.
Bishop, V.S.; Thames, M.D. and Schmid, P.G. (1984) Effects of
bilateral vagal cold block on vasopressin in conscious dogs. Am. J.
Physiol. 246(4 Pt 2), R566-569.
Yamashita, H. (1977) Effect of baro- and chemoreceptor activation
on supraoptic nuclei neurons in the hypothalamus. Brain Res.
126(3), 551-556.
Thames, M.D. and Schmid, P.G. (1979) Cardiopulmonary
receptors with vagal afferents tonically inhibit ADH release in the
dog. Am. J. Physiol. 237(3), H299-304.
Thames, M.D. and Schmid, P.G. (1981) Interaction between carotid
and cardiopulmonary baroreflexes in control of plasma ADH. Am.
J. Physiol. 241(3), H431-434.
Yamane, Y.; Nakai, M.; Yamamoto, J.; Umeda, Y. and Ogino, K.
(1984) Release of vasopressin by electrical stimulation of the
intermediate portion of the nucleus of the tractus solitarius in rats
with cervical spinal cordotomy and vagotomy. Brain Res. 324(2),
358-560.