Acciones óseas de las hormonas de la neurohipófisis / Bone actions of neuro hypophyseal hormones

La oxitocina (OXT) como la arginina-vasopresina (AVP) son dos hormonas primitivas secretadas por la hipófisis posterior. Sus receptores están mucho más ampliamente distribuidos en el organismo de lo que se pensaba originalmente, incluido el hueso. En los estudios preclínicos, la OXT ha mostrado ser anabólica para el hueso, promoviendo la osteogénesis sobre la adipogénesis y favoreciendo la actividad osteoblástica sobre la osteoclástica. Tanto los osteoblastos como los osteoclastos tienen receptores para la OXT, y los efectos de los estrógenos sobre la masa ósea en ratones está mediada por lo menos en parte por la OXT. El mecanismo preciso por el cual la activación de los receptores de oxitocina (OXTR) se traduce en un incremento de la formación ósea permanece poco claro. La AVP también podría afectar el esqueleto en forma directa. Dos de los receptores de la AVP, V1a y V2 están expresados en osteoblastos y osteoclastos. La inyección de AVP en ratones de tipo salvaje aumenta la formación osteoclastos que producen resorción y reduce los osteoblastos formadores de hueso. En forma opuesta, la exposición de precursores osteoblásticos a antagonistas de los receptores V1a o V2, incrementan la osteoblastogénesis, como también lo hace la deleción genética del receptor V1a. (AU)

Both oxytocin (OXT) and argininevasopressin (AVP) are primitive hormones secreted by the posterior pituitary gland. OXT receptors are much more widely distributed in the body than originally thought, including in bone. In preclinical studies, OXT has been shown to be anabolic for bone, promoting osteogenesis over adipogenesis and favoring osteoblastic over osteoclastic activity. Both osteoblasts and osteoclasts have receptors for OXT, and the effects of estrogen on bone mass in mice is mediated at least in part by OXT. The precise mechanism by which the activation of oxytocin receptors (OXTRs) results in an increase in bone formation remains unclear. AVP could also have direct actions on the skeleton. The two AVP receptors, V1a and V2, are expressed in osteoblasts and osteoclasts. Injection of AVP in wild-type mice increases the formation of osteoclasts increasing bone resorption, and reduces bone-forming osteoblasts. On the contrary, the exposure of osteoblastic precursors to V1a and V2 antagonists increase osteoblastogenesis, the same as the genetic deletion of the V1a receptor. (AU)

Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish.

RATIONALE: Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders. OBJECTIVES: This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists. METHODS: Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH(2)-d(CH(2))(5)-[D-Tyr(2),Thr(4)]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist. RESULTS: All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415. CONCLUSIONS: For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.

Diminished gray matter within the hypothalamus in autism disorder: a potential link to hormonal effects?

BACKGROUND: Subjects with autism suffer from impairments of social interaction, deviations in language usage, as well as restricted and stereotyped patterns of behavior. These characteristics are found irrespective of age, IQ, and gender of affected subjects. However, brain changes due to age, IQ, and gender might pose potential confounds in autism neuroimaging analyses. METHODS: To investigate gray matter differences in autism that are not related to these potential confounds, we performed a voxel-based morphometry analysis in 52 affected children and adolescents and 52 matched control subjects. RESULTS: We observed diminished gray matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin. CONCLUSIONS: This finding provides support for further investigations of the theory of abnormal functioning of this hormonal system in autism and potentially for experimental therapeutic approaches with oxytocin and related neuropeptides.

The role of hypothalamo-hypophyseal-adrenocortical system hormones in controlling pain sensitivity.

The present review addresses analysis of data demonstrating the role of the hypothalamo-hypophyseal-adrenocortical axis (HHACA) in controlling pain sensitivity. Experiments on rats have demonstrated the analgesic effects of exogenous hormones of all components of the HHACA - corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids - in the same models, and have also shown that the opioid and non-opioid mechanisms contribute to the development of the analgesia induced by these hormones. Endogenous glucocorticoids are involved in the development of analgesia mediated by non-opioid mechanisms. Along with the non-opioid mechanisms associated with endogenous glucocorticoids, the analgesic effect of ACTH can be mediated by the opioid mechanism. Unlike the situation with ACTH, the analgesic effect of CRH is mediated exclusively by non-opioid mechanisms, one of which is associated with HHACA hormones, while the other, appearing only on systemic administration, is not associated with these hormones. The actions of glucocorticoids on pain are mediated by neurons in the central gray matter of the midbrain.

Neurohypophysial hormone regulation of Cl- secretion: physiological evidence for V1-type receptors in sea bass gill respiratory cells in culture.

Neurohypophysial hormone receptors were studied in primary cultures of sea bass (Dicentrarchus labrax) gill respiratory-like cells grown on permeable supports. This preparation was previously shown to provide a functional model for investigating the hormonal regulation of Cl- secretion. Under control conditions, the cultured monolayered epithelium had a short-circuit current (ISC) of 3.5+/-1.1 micro A x cm(-2). This current had previously been identified as an active Cl- secretion. The addition of increasing concentrations of the fish neurohypophysial hormones, arginine vasotocin (AVT) or isotocin (IT), elicited a concentration-dependent stimulation of the ISC. Maximal increases of 60.9+/-12.1% and 117.7+/-28.0% above the basal ISC value were obtained for 10(-7) M AVT and IT respectively. Half-maximal effects were obtained for 3.1 x 10(-9) M AVT and for 1.4 x 10(-9) M IT. Mucosal application of 1.0 mM diphenylalamine-2-carboxylic acid (a specific blocker of Cl- channels) after serosal addition of 5 x 10(-8) M AVT or IT inhibited not only the basal but also the stimulated current, revealing a correlation with a hormone-dependent Cl- transport. Specific V1 or V2 receptor analogues of vasopressin (mammalian hormone) were used to characterize the type of neurohypophysial hormone receptors pharmacologically. While the V1 agonist [Phe2,Orn8]-oxytocin stimulated the basal Cl- secretion with a similar profile to that of AVT or IT, the V2 agonist [Deamino1,Val4,d -Arg8]-vasopressin had no effect. The V1 antagonist [d(CH2)5 1,O-Me-Tyr2,Arg8]-vasopressin used at a concentration of 5 x 10(-7) M totally reversed the 10-8 M AVT-stimulated Cl- secretion, whereas the V2 antagonist [d(CH2)5 1,d -Ile2,Ile4,Arg8,Ala9]-vasopressin used at the same concentration had no significant effect. In contrast, similar experiments carried out in the presence of 10(-8) M IT showed that both antagonists significantly reduced the IT-stimulated Cl- secretion, with the efficiency of the V1 receptor antagonist being significantly greater than that of the V2. This study provides evidence for neurohypophysial hormone control of Cl- secretion in fish cultured gill respiratory cells. It suggests that on a physiological basis the hormonal effect is shared by the two peptides present in fish neurohypophysis (AVT and IT), acting by means of two distinct, although pharmacologically similar, V1-type receptors (according to the mammalian classification). These specific receptors are expected to play an important role in controlling ion homeostasis in seawater fish.

Neurohypophyseal peptides in aging and Alzheimer's disease.

The neurohypophyseal hormones arginine-vasopressin (AVP) and oxytocin (OT) are produced in the neurons of the hypothalamic supraoptic (SON) and paraventricular (PVN) nucleus and in the much smaller cells of the suprachiasmatic (SCN) nucleus. The SON is the main source of plasma AVP. Part of the AVP and OT neurons of the PVN join the hypothalamo-neurohypophyseal tract, whereas others send projections to the median eminence or various brain areas, where AVP and OT are involved in a number of central functions as neurotransmitters/neuromodulators. AVP and OT from the PVN can also regulate via the autonomous innervation endocrine glands and fat tissue. OT is produced for a major part in the PVN but some OT neurons are present in the SON. Moreover, both AVP and OT containing neurons are observed in the "accessory nuclei", i.e. islands situated between the SON and PVN. The SCN is the biological clock, and the number of AVP expressing neurons in the SCN shows both diurnal and seasonal rhythms. In addition to these hypothalamic areas, AVP and OT may be found to a lesser extent in some other brain areas, such as the bed nucleus of the stria terminalis, diagonal band of Broca, nucleus basalis of Meynert, lateral septal nucleus, globus pallidus and the anterior amygdaloid nucleus, as well as in the peripheral tissues. The AVP and OT containing neurons should not be considered as one system. Prominent functional differences exist between the different nuclei. The heterogeneity also becomes clear from the marked differences in the neurohypophyseal peptides containing neurons of the SON, PVN and SCN during aging, and in the most prevalent age-related neurodegenerative diseases, i.e. Alzheimer's disease (AD). For those reasons, we will discuss the SON, PVN and SCN separately.

[Hormones of the posterior region of the hypophyseal gland]. / Hormoni zadnjeg reznja zlezde hipofize.

Arginine vasopressin is the main hormone involved in the regulation of body fluid osmolality. The hormone is released by the posterior pituitary whenever water deprivation causes an increased plasma osmolality or whenever the cardiovascular system is challenged by hypovolaemia and/or hypotension. The main site of action of this hormone is the renal collecting duct, but vasopressin is also a potent vasopressor and neurotransmitter, it has a role in the secretion of corticotrophin, in the regulation of the cardiovascular system, temperature and other visceral functions. Vasopressin also promotes the release of coagulation factors by vascular endothelium and increases platelet aggregability. In addition to its classical contractile effect on uterine myometrial and mammary glandular myoepithelial cells, oxytocin acts as neurotransmitter, stimulates endometrial prostaglandin production, pituitary prolactin secretion, luteolysis, sperm transport and natriuresis, and may play a role in immune function. Sensorial stimuli arising from the cervix and vagina as well as stimulation of the breast can induce secretion of oxytocin from the posterior pituitary. There are many vasopressin and oxytocin analogues (agonists and antagonists) that are synthetized with the goal of increasing duration of action and selectivity for the receptor subtypes, while non-peptide antagonists are orally active. The oxytocin and the vasopressin V1a, V1b and V2 receptors have recently been cloned and shown to form a sub-family within the large superfamily of G-protein-linked receptors. Renal V2 receptors mediate vasopressin-induced water reabsorption via induction of intracellular cAMP production in collecting duct cells. Most remaining actions of vasopressin on blood vessel constriction, liver glycogenolysis, platelet adhesion, adrenal angiotensin II secretion and certain brain functions are mediated via V1a-type receptors that are coupled to a Gq/11 protein. V1 receptor activation leads to stimulation of phospholipases C, D and A2, and an increase in intracellular calcium. Vasopressin stimulates pituitary corticotrophin release via a third vasopressin receptor type (V1b) which is present in corticotrophs. Oxytocin induces myometrial contraction, endometrial prostaglandin F2a production, mammary gland milk ejection, renal natriuresis and specific sexual, affilitative and maternal behaviours via oxytocin receptors which are also coupled to a G1/11 protein. Although only one oxytocin receptor type has been cloned so far, recent binding studies indicate that uterine endometrial oxytocin receptors may constitute a distinct receptor subtype. Expression of oxytocin receptors have relevant up- and down-regulation by oestrogens and progesterone.

Evidence for diverse pathways of hypophysiotropic hormone transport in mammals.

Comparative studies of mammalian hypothalamic-pituitary relationships have revealed striking variations in hypophysiotropic systems and in portal vascular architecture. Immunocytochemical studies indicate that mammalian GnRH, GHRH and somatostatin systems can project to all portions of the neurohypophysis (median eminence, infundibular stem and pituitary neural lobe). In rats, primary secretion sites are located within the median eminence and upper infundibular stem, whereas in bats, most projections extend into the lower infundibular stem and pituitary neural lobe. In ferrets and monkeys, sites of secretion appear to extend throughout the neurohypophysis, from median eminence to proximal neural lobe. In this review, these interspecific differences are examined in light of observed structural variations in portal vascular systems. Correlations suggest that hypophysiotropic hormones can be delivered to target cells in the pars distalis by diverse routes, with some species relying more heavily on long and others on short portal transport. These patterns may have important functional implications with respect to regulatory mechanisms operating within the hypothalamic-pituitary complex.

The neurohypophysial endocrine regulatory cascade: precursors, mediators, receptors, and effectors.

The neurohypophysial endocrine regulatory cascade has been described as a molecular model of neuroendocrine control of organismal functions. Any physiological function can be analyzed in molecular terms as a succession of interactions occurring either in a solution or in a membrane system. The key mechanism in the ordering of the cascade is the conformational recognition of the two partners at each step. Each interaction results in a change of conformation of a recognized protein that in turn becomes a recognizer for the following molecule. The cascade starts within the secretory cell by the processing of the expressed precursor along the secretory pathway until the storage of the mature mediator in vesicles and its subsequent exocytic secretion in blood. The circulating mediator recognizes the target cell through specific membrane receptors that transduce the message within this target cell. A second intracellular cascade leads to activation of the effector, the protein fulfilling the physiological function. The complexity of the messages is, in part, due to the duplication propensity of the genomic DNA, the frequent occurrence of multiple copies for precursors, mediators, receptors, and effectors, and therefore, a combinatorial diversity that increases during the course of evolution. Vertebrate neurohypophysial hormones can be ordered in two main evolutionary lineages, culminating in oxytocin and vasopressin in placental mammals. In this field, diversification of the messages was made by differential processing of the precursors, secondary gene duplications, the emergence of several types of receptors for each hormone, and a variety of effectors triggered by the second messengers within differentiated target cells. This review is an attempt to integrate neurohypophysial functions at the molecular, cellular, and organismal levels.

[Water homeostasis in amphibia: vasotocin and hydrins]. / L'homéostase hydrique chez les amphibiens: vasotocine et hydrines.

Water homeostasis is ensured in vertebrates through neuroendocrine reflexes involving hormones and specialized exchange organs depending whether the habitat is freshwater, sea or land. Amphibians have a development recapitulating two adaptive programs, first a freshwater fish program as a tadpole, then a land vertebrate program as an adult. The second, however, is imperfect because of the great evaporative water loss through the skin when the animal is in the open air. This loss must be compensated by water reabsorption through the nephron, the urinary bladder and mainly by water uptake through the skin. Water reabsorption by the nephron is not as efficient as in higher vertebrates but water uptake through the skin is crucial because adult amphibians, like tadpoles, do not drink. Adaptation occurred at the level of three organs, nephron, urinary bladder and skin whose permeability is under control of specific hormones. Aside from vasotocin, active on these three organs, differential maturation of provasotocin led to processing-arrested intermediates, namely vasotocinyl-Gly in virtually all anuran amphibians and vasotocinyl-Gly-Lys-Arg in Xenopus laevis. These intermediates result from a down regulation of the alpha-amidating enzyme or carboxypeptidase E, respectively. They have been termed hydrin 2 and hydrin 1 because they are endowed with hydroosmotic properties equal or superior to those of vasotocin on the skin and the bladder. However, in contrast to vasotocin, they are devoid of antidiuretic activity. Adaptive evolution has created, aside from the osmoregulatory vasotocin-nephron system that was preserved in strictly terrestrial nonmammalian tetrapods, additional functions such as the hydrin-skin and the hydrin-bladder rehydrations with specific messengers and organs. The adjuvant systems disappeared in true land vertebrates because the vasotocin-nephron system became more efficient.

Prolactin-releasing activity of neurohypophysial hormones: structure-function relationship.

Oxytocin (OT) and arginine vasopressin (AVP) have been reported to release PRL both in vivo and in vitro. The objectives of this study were 1) to compare the potencies of the PRL-releasing activities of OT and TRH using cultured anterior pituitary (AP) cells, and 2) to assess the PRL-releasing activity of naturally occurring neurohypophysial hormones and selected analogs. AP cells were incubated with peptides for 15 min, and medium PRL concentrations were determined by enzyme-linked immunosorbent assay. OT at 25, 100, and 400 nM increased PRL release by 110%, 175%, and 270%, respectively; higher concentrations (1600 and 6400 nM) did not cause a further increase in PRL release. TRH was 5-10 times more potent than OT on a molar basis. GH3 cells, a somatommamotroph tumor cell line, did not respond to OT and related compounds, but showed a similar responsiveness to TRH as AP cells. Twelve neurohypophysial peptides and selected analogs were incubated with AP cells, and their relative PRL-releasing activities were compared. OT and arginine vasotocin (AVT) showed the highest PRL-releasing activity. T4-G7-oxytocin, mesotocin, isotocin, lysine vasotocin, and AVP showed a moderate PRL-releasing activity, whereas, lysine vasopressin, desmopressin, tocinoic acid, pressinoic acid, and oxytocin free acid showed very low or no PRL-releasing activity. Coincubation of OT, AVT, or AVP with a specific OT receptor antagonist abolished their PRL-releasing activity. We conclude that 1) OT and related peptides are capable of stimulating PRL release in vitro, but their potencies are significantly lower than that of TRH; 2) unlike primary AP cells, GH3 cells are unresponsive to OT and related peptides; 3) AVT and AVP probably stimulate PRL release by acting via an OT receptor; and 4) the amino acid residues in positions 3 and 8 in the peptide chain and an amidated C-terminus are critical for the PRL-releasing activity of the neurohypophysial peptides.

Central nervous system effects of the neurohypophyseal hormones and related peptides.

This review of the CNS effects of the neurohypophyseal hormones and related neuropeptides discusses recent data illustrating the significance of these principles in brain function, synthesis, distribution, in particular in extrahypothalamic brain structures, binding sites, and signal transduction. Binding sites for vasopressin of the vascular V1a type have been found in the CNS and there is evidence for the existence of a subtype of the antidiuretic V2 receptor in the brain. Also two types of oxytocin binding sites have been detected. One widely distributed throughout the CNS is comparable to the uterine type receptor and a sexually dimorphic slightly different type is found in the ventromedial nucleus. Vasopressin and oxytocin can be converted to highly selective C-terminal fragments as AVP-(4-9) and OXT-(4-9) and shorter fragments. Conversely they can be acetylated. This almost completely blocks intrinsic activity in bioassays for central and peripheral effects. Such modifications are a good example of the plasticity of a neuropeptide system. For a number of CNS effects of the neurohypophyseal hormones, the whole molecule is required, as it is for their endocrine effects. This is the case for the influence of vasopressin on social communication, temperature regulation, epilepsy, and barrel rotation which may be an animal model of febrile convulsions, and some aspects of the central regulation of the cardiovascular system and for oxytocin on sexual behavior, social communication, and grooming. Nonendocrine C-terminal conversion products seem to exert their effects exclusively on the brain. These neuropeptides modulate learning and memory processes, social recognition, and rewarded behavior. The neuroendocrine and neuropeptide effect of vasopressin and oxytocin and related neuropeptides often exert their CNS effects in an opposite way. Neurochemical and electrophysiological studies suggest that norepinephrine, dopamine, serotonin, and glutamate are the neurotransmitters involved in the influence of the neurohypophyseal hormones and related neuropeptides on brain function. It appears that adequate amounts of vasopressin and oxytocin to induce these effects are released at the appropriate sites of action. It is postulated that the mix of neuropeptides released in the brain in response to environmental changes qualifies the behavioral, neuroendocrine, and immune response and the response of the autonomic nervous and vegetative systems of the organism. Although various other neuropeptides, such as those colocalized in vasopressinergic and oxytocinergic neurons, those produced in pro-opiomelanocortin (POMC) systems, and others, play a role in the modulation of adaptive responses, the neurohypophyseal hormones are unique in that their production sites in the hypothalamus serve the periphery, the pituitary, and the brain.

Metabolism of neurohypophysial hormones.

Over the past decade several new routes of neurohypophysial hormone metabolism have been identified. These include nonhepatic splanchnic clearance and renal clearance in addition to filtration that appears to be receptor mediated. The intraluminal degradation of VP in the proximal tubule, and distal tubular secretion, at least in one species, has been identified. The brain has been identified as a site for VP and OT metabolism, and the amniotic sac may be a major site for VP clearance in the guinea pig fetus. There have been generalized findings regarding VP and OT metabolism. First, VP metabolism in the whole body and in the amniotic sac appears to increase with increasing concentrations of hormone; this does not appear to be the case with OT. Also, evidence has been presented that suggests a potential for the formation of biologically active metabolites. There have been several associations of pathophysiological states with altered VP or OT metabolism, sometimes with plasma levels remaining unchanged. Lastly, caution is emphasized when measuring these hormones by RIA, and differences in specificities of antisera toward hormone metabolites must be considered.

Neurohypophysial hormones and circadian rhythm.

In conclusion, neurohypophysial hormone levels in human plasma and in the plasma, pituitary, and hypothalamus of the rat show clear rhythms over the 24-hour period. These are not true circadian rhythms, as they may be modified by a number of factors, including the stage of the estrous cycle and hydrational status. There is evidence to suggest that the patterns observed may in part reflect the action of the pineal product melatonin. Pinealectomy influences the pattern of hormone release, while melatonin and its analogues inhibit hormone release, although the major circulating metabolite has no effect.