role of central and peripheral chemoreceptors
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Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, 13, 000-000 1
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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-Bötzinger 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: [email protected]
(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, acid-base 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
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2 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3 Iovino et al.
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 P2X-receptors 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-
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.
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Role of Central and Peripheral Chemoreceptors in Vasopressin Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3 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 re-entry 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 chemo- receptors, 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 chemo- receptors, 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 baroreceptor-mediated 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 alpha2-adrenoceptor 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 chemo- receptor 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
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4 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3 Iovino et al.
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 50°C increases plasma AVP concentration from four to fivefold [54].
AFFERENT PATHAWAYS FROM RENAL CHEMO-
RECEPTORS 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.
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
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.
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Role of Central and Peripheral Chemoreceptors in Vasopressin Endocrine, Metabolic & Immune Disorders - Drug Targets, 2013, Vol. 13, No. 3 5
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Received: 24 March, 2011 Accepted: 29 March, 2012