Pituitary (2016) 19:345–355

DOI 10.1007/s11102-015-0703-0

Arginine vasopressin (AVP): a review of its historical perspectives,

current research and multifunctional role in the hypothalamo-
hypophysial system
Fabio Rotondo1 • Henriett Butz1 • Luis V. Syro2 • George M. Yousef1 •
Antonio Di Ieva3 • Lina M. Restrepo4 • Andres Quintanar-Stephano5 •
Istvan Berczi6 • Kalman Kovacs1

Published online: 13 January 2016

Ó Springer Science+Business Media New York 2016

Abstract vasopressin-producing cells and their hormone secretion

Introduction This publication reviews the function of requires further investigation.
arginine vasopressin and focuses on the morphologic and
functional correlation between the hormone and its effect on Keywords Arginine vasopressin
Corticotroph cells

stress, the hypophysial–adrenocortical axis, neuroimmune Hypothalamus
Pituitary
Receptors
responses, renal function and corticotroph pituitary tumors.
Materials and methods A literature review was per-
formed using various search engines for information Background
regarding the morphology and the multifunctional role of
arginine vasopressin. Without accepting the fact that everything changes and that
Results Although a large number of studies were pub- old problems need to be regarded from a new angle, we
lished discussing these interactions, there are several cannot advance in our study of science. This perspective also
important areas that are still obscure. holds true when considering the function of the hypothala-
Conclusion The questions of how does arginine vaso- mus and the pituitary gland. Earlier, it was thought that the
pressin affect the morphology and function of these various hormones (which were originally termed ‘‘components of
areas, and how does the secretion of ACTH and adreno- the pituitary gland’’) oxytocin and vasopressin, were pro-
cortical hormones influence the morphology of arginine duced in the posterior lobe of the pituitary [1]. Then, in the
early 1950s Vincent du Vigneaud was able to synthesize and
& Fabio Rotondo
describe the structures of both oxytocin and arginine vaso-
[email protected] pressin (AVP) [2, 3] which led to du Vigneaud winning the
Nobel Prize in 1955. Howard Sachs and his associates were
1
Division of Pathology, Department of Laboratory Medicine, then able to demonstrate that AVP first appeared in the
Keenan Research Centre for Biomedical Science, Li Ka
Shing Knowledge Institute, St. Michael’s Hospital, 209
hypothalamus and then transported to the posterior pituitary
Victoria Street, Toronto, ON M5B 1T8, Canada and not how it was first thought [4–6].
2
Department of Neurosurgery, Hospital Pablo Tobon Uribe
Initially, it was believed that besides oxytocin, which will
and Clinica Medellin, Medellı́n, Colombia not be discussed here, there were two neurohypophysial
3
Department of Neurosurgery, Macquarie University Hospital,
hormones: vasopressin and antidiuretic hormone. The
Sydney, Australia function of the former was vasoconstriction and blood
4
Division of Endocrinology, Clinica Medellin, Medellı́n,
pressure control, while the role of the second hormone:
Colombia antidiuretic hormone was to absorb water from the renal
5 tubules leading to antidiuresis. Absence of this hormone
Departamento de Fisiologı́a y Farmacologı́a, Centro de
Ciencias Básicas, Universidad Autónoma de Aguascalientes, would cause diabetes insipidus, a rare metabolic disorder
Aguascalientes, Mexico characterized by polyuria and polydipsia [7–9]. Since the
6
Department of Immunology, Faculty of Medicine, University publication of these studies, there has been a plethora of
of Manitoba, Winnipeg, Canada research that provided conclusive evidence that, besides

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oxytocin, there was only one hormone: arginine vasopressin their patterns of recognizing AVP analogs expressed in
(AVP), which was responsible for both vasoconstriction and the brain as well as in the periphery [20, 21]. AVP
antidiuresis. However, this has also proved to be a miscon- receptors are guanine nucleotide-binding protein coupled
ception in regards to the role of AVP. The idea that it had only receptors (GPCRs). V1a receptors are mainly expressed
two effects: vasoconstriction and antidiuresis was not on vascular smooth muscle cells and myometrium where
entirely true. Currently, there is conclusive evidence that they mediate vaso- and myocontraction, respectively, and
AVP is a crucial hormone that has a multitude of functions in on hepatocytes and platelets as well, where they are
several organs. involved in glycogenolysis and platelet aggregation
(Fig. 1). In the central nervous system, V1a receptors
have been reported to regulate circadian rhythm [22],
Physiology body temperature [23], social behavior, social cognition
and emotion [24]. They also play a crucial role in the
AVP or antidiuretic hormone, is a hypothalamo-neurohy- development of psychiatric disorders such as anxiety,
pophysial peptide which is involved in homeostasis by depression and post-traumatic stress disorder [25]. V1a
regulating water absorption in the renal tubules and by receptors are also present in other tissues including the
vasoconstriction [10]. It has also been shown that AVP brain, adrenal cortex and adipose tissue [20, 26]. V1b
plays an important role in modulating pituitary functions, receptors are prominently expressed in corticotroph cells
stress, immune response and behavior [11–13]. AVP is a of the anterior pituitary and modulate ACTH release
mammalian peptide that has been evolutionarily conserved [27]. They are also involved in various cognitive func-
and appears to precede the bifurcation of the vertebrate and tions in the brain [20, 28]. Depending on its expression
invertebrate lineages [14, 15]. level, V1b receptors were described to couple to Gq
AVP is a small peptide consisting of nine-amino acids alone or in combination with Gi, and may also recruit
with a disulfide bridge between two cysteine amino acids several Gs proteins activating several signaling pathways
which is synthesized in the paraventricular (PVN) and [29]. It was suggested that increased cAMP levels in
supraoptic nuclei (SON) of the hypothalamus while smaller cells expressing medium or high V1b receptors may
quantities are also produced by various tissues outside the represent crucial events in the genesis of corticotroph
hypothalamus. AVP production within the hypothalamus is tumors [30]. The main function of V2 receptors are in
encoded, along with two associated proteins, neurophysin 2 the kidney [20]. V2 receptors are present on the baso-
(NPII) and a glycopeptide, copeptin by than AVP gene, lateral membrane of the collecting tubules of the kidney
located in chromosome region 20p13 [16, 17]. AVP is pro- and upon ligand binding, leading to aquaporin-2 water
duced as the precursor prepro-vasopressin, composed of 164 channel insertion to the apical membrane and also to
amino acids, packaged into neurosecretory granules and aquaporin-2 synthesis. As a result, AVP increases water
transported axonally in the stalk to the posterior pituitary. On permeability and water reabsorption. V2 receptors are
the way to the neurohypophysis, AVP is processed into the also active in the loop of Henle of the kidneys where
active hormone, where it’s stored for secretion [16]. The they stimulate Na? reabsorption. Therefore, AVP
synthesis of AVP involves precursor peptides, prepro-va- defect—resulting from decreased AVP release or
sopressin (pre-proAVP) and provasopressin (proAVP) that decreased renal sensitivity—leads to diabetes insipidus, a
are enzymatically cleaved into the vasopressin, NPII and condition characterized by polyuria, polydipsia and
glycopeptide copeptin. These three products are all released hypernatremia. V2 receptors are also found outside the
into the circulation in equal ratios. AVP gene is composed of kidney. Extrarenal V2 receptors are located in endothe-
three exons. Exon1 encodes the signal peptide, AVP and the lium [20] where the receptor activation by high levels of
NH2-terminal region of the NPII. Exon 2 encodes the central desmopressin and by equal concentrations of endogenous
region of the NPII and exon 3 on the COOH-terminal region AVP in the blood leads to the release of von Willebrand
of the NPII and copeptin peptide, a surrogate marker of factor (vWF) and Factor VIII (FVIII) from Weibel–
vasopressin secretion, which is also secreted along with AVP Palade bodies [31]. Both vWF and FVIII are two distinct
in equal amounts [18, 19]. but related glycoproteins that are synthesized and stored
within the same cell and they circulate in blood plasma
as a bound complex [32] (Table 1). To our knowledge,
Arginine vasopressin receptors the role of V2 receptor in tumor development and pro-
gression has not been elucidated but studies have shown
Arginine vasopressin activity occurs primarily through its its presence in transformed epithelial cells including
receptors. Three different AVP receptors (V1a, V2 and lung, breast, and cervical cancers as well as in pituitary
V1b) have been identified and can be distinguished by corticotroph adenomas [33–36].

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Pituitary (2016) 19:345–355 347

Fig. 1 Schematic representation of the role of arginine vasopressin (AVP) on corticotroph cells of the pituitary gland in its pathophysiological
spectrum

AVP effect on the kidney in the kidneys when filtering the blood stream [37, 38].
This function of AVP is crucial to maintain proper serum
The primary function of AVP in the kidney is to decrease osmolarity.
water excretion and to increase urine osmolarity [37, 38]. In conditions where the kidney is unable to respond to
Acting via V2 receptors located in the collecting ducts of AVP due to disease or damage, there is a decreased ability
the kidney, AVP is able to increase water permeability to remove water which results in nephrogenic diabetes
which results in the regulation of extracellular fluid volume insipidus (NDI) [43, 44]. Pituitary function is normal and
in the kidneys [37, 39–41]. High levels of AVP causes the AVP levels are normal in NDI. Causes of NDI include
kidney to reabsorb more water which leads to decreased genetic mutations in the V2 receptor or acquaporin-2 gene
urine formation [37]. As a result, this effect may increase which impedes the normal function of the kidney, poly-
blood volume, cardiac output and arterial pressure [38, 42]. cystic kidney disease, electrolyte imbalance, amyloidosis,
AVP is also involved in maintaining proper electrolytic sickle cell disease, Sjogren syndrome, low blood potassium
balance in the blood stream by controlling water retention and high blood calcium [45–49]. Treatment for NDI

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Table 1 Effect of Arginine vasopressin (AVP) by receptors: location and function [20–32]
Receptor Location Signaling Functions
pathways

V1a Vascular smooth muscle, Platelets, Hepatocytes, G-protein Vasocontstriction, myocontraction, platelet aggregation,
Myometrium, adrenal cortex coupled glycogenolysis, uterine contraction, circadian rhythm, regulation
of body temperature, social behavior, social cognition, emotion,
ACTHa release in the adrenal gland
V1b Corticotroph cells of anterior pituitary, chromaffin G-protein ACTHa release in response to stress and in the adrenal gland,
cells in adrenal medulla coupled cognitive function in the brain
V2 Basolateral membrane of collecting tubules of the G-protein Insertion of aquaporin-2 water channels into apical membrane,
kidney, loop of Henle of kidney, Vascular coupled induction of aquaporin-2 synthesis, stimulates Na? reabsorption,
endothelium releases von Willebrand factor (vWF) and Factor VIII from
Weibel–Palade bodies
a
ACTH indicates adrenocorticotrophic hormone

commonly includes the administration of Thiazide which ACTH and corticosterone levels in wild type animals
increases water and solute excretion thereby reducing compared to V1b knockout animals [60]. In contrast,
serum osmolarity [45, 50]. In contrast to NDI, neurogenic ACTH response to acute stress factors was significantly
(central) diabetes insipidus (CDI) is characterized by abated in AVP1b receptor knockout mice compared to the
polyuria and volume depletion resulting from a deficiency wild-type [60]. There was also a reduction in the plasma
in secretion of AVP from the posterior pituitary [45]. corticosterone concentrations in the knockout mice in
Although AVP is released from the posterior pituitary, it is response to change in environment. This reaction was not
produced in the hypothalamus thus the cause of CDI may seen when the knock-out mice were exposed to mild
be a result of either failure and/or defect in the hypotha- restraint or forced swim stress [60].
lamus or poster pituitary to produce or release AVP in During chronic stress, CRH stores remained unchanged
adequate amounts or to transfer the hormone via the stalk but there was an increase in AVP stores and in CRH nerve
to the posterior lobe [45]. Other causes of CDI include terminals [61]. In repeatedly stressed rats, V1b receptor
damage or tumor to the pituitary gland [45], tumors expression was increased in pituitary contrary to CRH,
involving the hypothalamus, head trauma, and in 10–30 % which exhibited down-regulation of CRH binding [62–64].
of cases, CDI results from idiopathic causes [45, 51–53]. It However, ACTH itself, in the absence of AVP, is still
has also been shown that there may be a genetic link to this sufficient to elicit full adrenocortical glucocorticoid
type of diabetes insipidus [51, 54, 55]. Perrotta et al. [56] response, and the increase of vasopressinergic activity is a
sequenced both AVP and Wolframin (WFS1) genes in nine major determinant of ACTH responsiveness to a novel
children with CDI and found that early-onset CDI is stressor during chronic stress [62]. Studies have shown that
associated with de novo mutations of the AVP gene and during chronic stress, the HPA axis regulation switches
hereditary changes in the WFS1 gene [56]. from CRH to AVP, and pituitary V1b receptors become up-
regulated, suggesting that AVP has a primary role in the
HPA axis adaptation to long-term stress stimulation [62].
AVP effect in stress

AVP is co-secreted with CRH and mainly potentiates its AVP effect on hypothalamus–pituitary–adrenal
effect thereby indicating that AVP has a secondary role in (HPA) axis
stress response. Recently, it has been demonstrated that
apart from this secondary influence, AVP acts as a direct The endocrine system, along with the nervous and circu-
regulator in stress and immune responses [11]. latory systems, plays a critical role in the integration and
In acute stress, AVP expression and secretion rapidly coordination of many functions within the body. The role
increases-similar to CRH and ACTH [57, 58], and AVP of the endocrine system in maintaining homeostasis within
contributes to the full ACTH response [59]. Knock-out the body would not be possible without the melding of the
experiments have demonstrated that V1b receptor is two other systems. For example, the basal secretion of
required for intact ACTH response [57, 60]. Acute stress glucocorticoids is essential for homeostasis including
factors (e.g. restraint or forced swim) elevated both plasma metabolism, endocrine regulation, as well as the

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cardiovascular, nervous and immune systems. Even small CRH hypophysiotropic neurons in pPVN also produce
alterations from their normal circulating levels and diurnal other peptides apart from CRH. For instance, AVP, neu-
rhythm can lead to changes of physiological conditions and rotensin, encephalin, GABA, angiotensin 11, cholecys-
biochemical parameters. tokinin (CCK), galanin, vasoactive intestinal peptide (VIP/
The hypothalamus is the primary link between the PHI) or thyrotropin-releasing hormone (TRH) have all
endocrine system and the central nervous system (CNS). been documented in various studies to be produced by
Stimuli originating either within the CNS or outside the CRH hypophysiotropic neurons (reviewed in [72]). In
CNS are integrated by the hypothalamus. Responses to the regards to AVP, there is little information regarding the
stimuli originate along the hypothalamo-pituitary axis. The physiological importance of the co-secretion of the sub-
hypothalamus can also control the function of the adrenal stances, which are co-stored with CRH [72]. It has been
cortex and thyroid glands via the pituitary. reported that AVP, which is involved in the physiological
Glucocorticoid blood levels are centrally regulated by control of ACTH secretion, appears to originate primarily
the hypothalamus, which is a target of diverse neuronal and from AVP co-storing CRH pPVN neurons rather than
endocrine inputs. The hypothalamic paraventricular magnocellular PVN [72]. It was also noted that AVP
nucleus (PVN) is responsible for producing the secreted by pPVN is independent from osmotic status and
hypophysiotropic releasing and inhibiting hormones [23]. increases during stress [62]. In vitro studies demonstrated
The hypothalamic PVN has two major parts: the magno- that in rat anterior pituitary cells exposed to AVP before
cellular (mPVN) and parvocellular (pPVN) nucleus; and in CRH, CRH did not potentiate AVP-stimulated secretion of
addition, a more caudal cell group [65]. The mPVN (along ACTH [73]. It can be suggested that both AVP and CRH
with the supraoptic nucleus) neurons project to the poste- cooperate to regulate ACTH release based on the fact that
rior pituitary, where they release AVP and oxytocin (OT) the presence of AVP and CRH in the same pPVN neurons
into the peripheral circulation whereby they are responsible together with the fact that CRH cannot potentiate AVP-
for the ‘‘systemic’’ effect of the secreted peptides. Neurons stimulated ACTH secretion.
from the caudal part project to autonomic structures and Under certain stimuli (i.e. stress), the HPA-axis releases
contain corticotroph releasing hormone (CRH also known ACTH from the anterior pituitary which stimulates the
as CRF), AVP, and OT peptides. The pPVN is the structure adrenal cortex to release glucocorticoids. AVP mainly
where hypophysiotropic CRH secreting neurons are loca- influences the release of ACTH by acting on V1b receptors
ted, and which project to the median eminence and release located in the pituitary but it can also coactively heighten
CRH into the hypophysial portal circulation (Fig. 1). The the actions of CRH to influence ACTH release [74]. In
anterior pituitary is vascularized by the hypophyseal portal addition to its stimulatory activity on the anterior pituitary,
vessels that arise from the median eminence capillaries and AVP can also stimulate adrenocortical hormone release in
deliver hypothalamic hormones to the adenohypophyseal the adrenal gland by acting on V1a and V1b receptors
corticotroph cells where CRH interacts with its receptor located in the adrenal cortex and on the chromaffin cells in
resulting in the stimulation and secretion of adrenocorti- the adrenal medulla, respectively [75].
cotropic hormone (ACTH) and other pro-opiomelanocortin
(POMC)-derived peptides (POMC, ACTH precursor) [66,
67]. In the adrenal cortex, ACTH induces glucocorticoid AVP effect on neuroimmune responses
secretion from the zona fasciculata. The adrenocortical
glucocorticoids, among others, inhibit the synthesis and AVP is capable of perpetuating both innate and adaptive
secretion of hypothalamic CRH and POMC-derived pep- immunity because of its ability to stimulate both the HPA
tides in the pituitary in a negative feedback manner [68, axis and prolactin (PRL) secretion [11]. As a result, AVP is
69]. proving to be a vital immunoregulatory peptide. The
Hypophyseal CRH receptors, known as CRH-1 receptor, function of AVP during conditions of acute phase reaction
are Gs protein–coupled membrane receptors and ligand (APR) or chronic inflammation differs significantly [11].
binding on corticotroph cells lead to increased intracellular While the levels of AVP rise together with CRH during
cAMP production, which in turn, results in increased APR, CRH levels are repressed in conditions of chronic
POMC synthesis and increased release of ACTH and b- inflammation. As a result, AVP acts as the primary
endorphin, a protein product of POMC [70]. Apart from immunoregulator in the hypothalamus during states of
CRH, which is considered as the major hypothalamic chronic inflammation whereas during APR, AVP plays a
releasing factor for ACTH, other hypothalamic compounds secondary role as CRH regulates the systemic inflamma-
such as vasopressin, oxytocin, and norepinephrine may also tory process [11].
have some stimulatory effect on anterior pituitary ACTH Studies have shown that rats with higher AVP serum
release, or they can potentiate CRH-effect [71]. levels have increased susceptibility to inflammatory and

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autoimmune diseases and low serum AVP levels are autologous mixed lymphocyte response in vitro. AVP
associated with decreased inflammatory response [76, 77]. effects on immune cells are mediated by V1a, V1b and V2
Berczi et al. [11], demonstrated that apart from vaso- receptors [89, 92–96] and Quintanar-Stephano et al. [89],
pressin, growth and lactogenic hormones (GLH) and pla- noted that AVP induced IL-2 may be the AVP affect
cental lactogens also control adaptive immunocompetence. mediator on immune response.
GH and PRL levels become elevated in endotoxemia
together with CRH and AVP [11]. Hypophysectomy sup-
pressed inflammation was antagonized by pituitary graft AVP effect on pituitary corticotroph tumors
implantation or by PRL administration [78]. It was found
that PRL stimulated erythropoiesis and together with GH Although the majority of pituitary corticotroph tumors are
they play an important role in the regulation of bone microadenomas measuring less than 10 mm in diameter,
marrow cell growth and function. It was demonstrated that most silent pituitary corticotroph adenomas are
DNA and RNA synthesis is GLH dependent not only in macroadenomas ([10 mm diameter) [97]. It is uncertain
bone marrow but in thymus and spleen as well [79]. Berczi whether pituitary corticotroph adenomas arise from the
et al. [11] found that ACTH and glucocorticoid hormones pituitary or if there is a primary defect in the hypothalamus
were able to impede this effect on hypophysectomized rats. [98].
Glucocorticoids and catecholamines stimulate the growth AVP is described as a weak stimulator on its own [62,
of suppressor T-cell population and by that suppressive 99], but it can still stimulate ACTH secretion in cultured
adaptive immunity. In this regard, AVP has a balancing human corticotroph cells [100]. Various studies have
role through regulating the HPA axis (innate immune shown that AVP mainly stimulates ACTH secretion via
function) and through PRL secretion (adaptive immunity) activation of V1b receptor in the pituitary, but it may also
[77]. act, in part, via the hypothalamus to stimulate CRH
Injury, inflammation or infections can induce the same secretion [13, 101]. The presence of AVP receptors on
cytokine secretion/effect as those seen during psychologi- tumor cells is utilized in clinical practice [99]. Desmo-
cal stress [80]. Several studies demonstrated that leukemia pressin (dDAVP), a long-acting synthetic analogue of
inhibitory factor (LIF), IL-1b and IL-6 can increase AVP, is often used for discriminating ACTH-dependent
hypothalamo-pituitary-adrenal axis activity and/or ACTH Cushing disease from ectopic ACTH syndrome or normal
secretion [81–83] Specifically, peripheral administration of condition [102]. dDAVP is a selective V2 receptor agonist
IL-1b increased CRH, c-fos and AVP mRNA expression in and is the choice for the treatment of patients with diabetes
hypothalamic pPVN [84–86] and POMC mRNA in the insipidus. Normal pituitary corticotroph cells express V1b
anterior pituitary [84]. Following IL-6 injections, plasma receptor, but it was reported that apart from V1b, V1a
AVP levels were noted to be elevated [83], and although it receptors, CRH receptors were also abundantly expressed
had no effect on mRNA expression, it did increase circu- in most of the pituitary corticotroph adenomas [103].
lating ACTH and corticosterone levels [84] as well as PRL. However, V2 receptor expression showed great variability,
Immunoneutralization of AVP was reported to decrease and a positive correlation was also found between stimu-
plasma ACTH response to peripherally administered IL-1b lated ACTH increase and the degree of V2 receptor
in certain times [80, 87], and stronger effect following expression [103]. V1b receptor was reported to be over-
intraventricular administration [86]. It was concluded that expressed in pituitary corticotroph adenomas compared to
the role of AVP in peripheral IL-1b induced ACTH normal pituitaries [104]. Transgenic mice overexpressing
secretion was permissive to the full ACTH response but V1b receptor showed similar basal ACTH level to controls
activational after intracerebroventricular IL-1b treatment to but moderately increased corticosterone levels and aug-
the CRH effect [80, 86]. These findings can be supported mented response to AVP which suggest that the negative
by analyzing the role of AVP in immune functions in glucocorticoid feedback may be altered at the pituitary
neurointermediate pituitary lobectomized (NIL) rats. It was level [104]. Thus, a possible explanation to account for the
demonstrated that AVP serum levels in rats with NIL were change in expression of V1b and V2 receptors, is that the
lower, which caused a decrease in their cell-mediated high level of circulating corticosteroids are the conse-
hormone response [88]. This is due to the fact that AVP is quence and not the cause of hypersecretion in corticotroph
the biologically active peptide hormone that is formed by tumors. However, the debate over the role of an increased
processing the prohormone proAVP in NIL. In similar expression of V1b receptors in pituitary corticotroph
studies, NIL animals presented decreased humoral and cell- tumors is ongoing to permit a definitive conclusion.
mediated immune response [89–91], and that the latter It was also shown that AVP can mediate proliferative
could be restored by desmopressin administration [89]. signals in different cell types including fibroblasts, bone
Bell et al. [92] demonstrated that AVP enhanced the marrow, mesangial or liver cells [105–108]. In vitro AVP

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is also able to stimulate growth of corticotroph cell line cells by activating TREK-1 channels while CRH, acting via
[109] and chronic stress leads to increased number of the cAMP dependent pathway could inhibit those same
corticotophs after adrenalectomy which supports the idea channels and cause them to depolarize. Thus, hyperpolar-
that AVP can mediate proliferative signal in vivo as well ization is possible from the formation of AA in corticotroph
[110]. In regards to the lack of co-localization of ACTH in cells after CRH stimulation and this action can, in turn, limit
mitotic cells, it has been suggested that new corticotroph depolarization resulting from CRH activity. These findings
cells may be recruited from undifferentiated cells [62, 110]. illustrate how CRH and AA simultaneously regulate the
However, there are studies emphasizing that anterior activity of TREK K? channels and the role of these channels
pituitary trophic responses after adrenalectomy are more on the resting potential in corticotroph cells [122].
likely to be mediated through direct glucocorticoid with-
drawal at the level of the pituitary rather than via changes
in hypothalamo-hypophyseal releasing factor exposure Clinical use of AVP effect on HPA
[111]. AVP effect on corticotroph cells may shed new light
on corticotroph tumorigenesis. There are several biochemical tests that can demonstrate the
Cushing’s syndrome (CS), or hypercortisolism, is a effect of AVP on HPA and they are widely used in the dif-
hormonal disorder caused by prolonged exposure of the ferential diagnosis of Cushing disease. The Desmopressin
body to high levels of cortisol from an adrenocortical test has been used for the differential diagnosis of ACTH-
tumor or by ACTH-independent hyperplasia. A study by dependent CS [122]. AVP stimulates ACTH release via the
Horiba et al. [112], suggested that AVP may play a role in V1b receptor, particularly from ACTH-producing pituitary
the pathophysiology of CS. It was shown that tumor cells adenomas. Desmopressin (dDAVP), a preferential V2 and
that cause CS had either a V1a receptor mutation which V1b vasopressin receptor agonist, causes a significant rise in
caused an increase in sensitivity to AVP or over-expressed ACTH and cortisol in 80–90 % of patients with Cushing
V1a receptors which resulted in an increase of corticos- disease and only in occasional patients with the ectopic CS
teroid secretion [112]. The role of AVP in the development [122, 123]. Although its overall sensitivity and specificity are
and progression of pituitary corticotroph adenoma is a very lower than that of the CRH test, it can be applied when CRH
important area and needs further studies. It may be that is not available [124] or they can be used in combination to
more knowledge would lead to new treatment options in increase the discriminatory value above either test alone
patients with pituitary corticotroph adenomas. [125]. The Desmopressin test may be useful in the diagnosis
of pseudo-Cushing states [126] where it seems to have a
higher effectiveness with respect to the combined dexam-
Ca1 and K1 effect on corticotroph cells ethasone (suppression)—CRH (stimulation) test [127].
Bilateral inferior petrosal sinus sampling (BIPSS) along
Research focusing on AVP and CRH revealed the impor- with CRH stimulation provides the most accurate and
tance of Ca? in cAMP effects on hormone secretion. In the reliable test for distinguishing between pituitary from non-
presence of CRH, ACTH secretion in the corticotrophs via pituitary ACTH-dependent CS [128], and currently repre-
AVP stimulation of Ca? mobilization from the endoplasmic sents the gold standard in the differential diagnosis since it
reticulum is substantially enhanced [113]. Normally, AVP is can confirm the central source of ACTH [129]. It is rec-
a very weak secretagogue and one of the roles of CRH in ommended in patients with CS in whom clinical, bio-
corticotroph cells is to modulate spontaneous electrical chemical or radiological studies are discrepant in
activity and facilitate Ca? entry into the cells [113]. CRH identifying the site of ACTH production. In the BIPSS
modulates the resting membrane potential and rate of technique, CRH is administered to the patient during the
depolarization in corticotroph cells causing them to become procedure. CRH acts synergistically with AVP to cause
active [114, 115]. Studies have demonstrated that depolar- significant secretion of ACTH in patients with Cushing’s
ization and activation of voltage-gated Ca2? channels in disease [130].
mouse corticotroph cells is accomplished by stimulating
CRH receptors, which reduce the background K? current
[116, 117]. It was also shown that in rat pituitary cells, CRH Conclusion
induces the release of arachidonic acid (AA) [118, 119]. The
precise role of AA in ACTH secretion has yet to be defined. Earlier, it was thought that AVP had only two effects:
Patel and Honoré [120] demonstrated that AA was able to vasoconstriction and antidiuresis. This concept completely
activate TREK K? channels, which are involved in setting changed. Currently, it is known and widely accepted that
the resting potentials in various cell types. Lee et al. [121] AVP exhibits diverse effects through its three receptors on
found that AA was able to hyperpolarize mouse corticotroph different cell types. It has multiple regulatory functions in

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