Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia.

OBJECTIVE: Controversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction. DESIGN: The study was conducted in a single Pediatric Endocrinology Research Unit. METHODS: Forty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed. RESULTS: Mean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, P<0.0001). Group 5 showed higher mean Posm and lower mean AVP at all time points (P<0.0001). Mean thirst score did not show a significantly different trend between the groups 1 and 2. Urine osmolality was above 750 mosm/kg in all but seven patients after osmotic challenge. CONCLUSIONS: Patients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.

[Vasopressin and angiogenesis]. / Vasopressine et angiogenèse.

In adult mammals, the CNS vasculature remains essentially quiescent, excepted for specific pathologies. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within the hypothalamic magnocellular nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. Using more appropriate techniques, we first demonstrated that in these nuclei, the proliferative response to osmotic stimulus is essentially associated with local angiogenesis. We then showed that hypothalamic magnocellular neurons express vascular endothelial growth factor (VEGF), a potent angiogenic factor, that plays a major rôle in the angiogenesis induced by osmotic stimuli. We then demonstrated a correlation between increased VEGF secretion and local hypoxia. In AVP-deficient Brattleboro rats, the dramatic activation of magnocellular hypothalamic neurons failed to induce hypoxia, VEGF expression or angiogenesis suggesting a major role of hypothalamic AVP. Lastly we showed that 1) hypoxia and angiogenesis were not observed in non-osmotically stimulated Wistar rats in which circulating AVP was increased by the prolonged infusion of exogenous AVP, 2) contractile arterioles afferent to the magnocellular nuclei were strongly constricted by the perivascular application of AVP via V1a receptors (V1a-R) stimulation, and 3) following the intracerebral administration of selective V1a-R antagonist to osmotically stimulated rats, hypothalamic hypoxia and angiogenesis were inhibited. Together, these data strongly suggest that the angiogenesis induced by osmotic stimulation relates to tissue hypoxia resulting from the constriction of local arterioles, via the stimulation of perivascular V1a-R by AVP locally released from dendrites.

Cannabinoid-mediated regulation of the hypothalamo-pituitary-adrenal axis in rats: age dependent role of vasopressin.

OBJECTIVE: Adaptation to stress is a fundamental component of life and the hypothalamo-pituitary-adrenocortical axis (HPA) plays a crucial role in it. The place of cannabinoid influence seems to be in the brain, especially where corticotropin releasing hormone and vasopressin (AVP) secreting neurons are located. The role of AVP is considered to be more important in young than in adult rats. Here we addressed the question if cannabinoid-mediated regulation of the HPA involves AVP and if there is any difference between young and adult rats in this process. METHODS: 10-day-old and adult AVP deficient Brattleboro rats were compared with their heterozygous littermates 1h after WIN 55,212-2 (6mg/kg i.p.) injection. RESULTS: In control animals the injection led to elevated adrenocorticotropin (ACTH) and corticosterone hormone levels at both ages without remarkable age difference in ACTH levels while all corticosterone levels of adults was approximately 10-times higher. The ACTH secretion of young AVP deficient rats failed to react to WIN 55,212-2 injection while their corticosterone levels were even higher than their littermates. In contrast in adult the role of AVP was diminished. CONCLUSIONS: We can conclude that the peripheral administration of cannabinoids leads to HPA axis stimulation, which process involves AVP at least in the young rats. The discrepancy between ACTH and corticosterone levels in young rats suggests an alternative adrenal gland regulatory pathway, which might be present in all studied animals. However, it comes to the front just in AVP deficient pups.

Congenital vasopressin deficiency and acute and chronic opiate effects on hypothalamo-pituitary-adrenal axis activity in Brattleboro rats.

A growing body of evidence suggests that vasopressinergic activity in the hypothalamus is important in stress-related behaviors (like drug abuse) in line with a role in the regulation of the hypothalamo-pituitary-adrenal axis (HPA). We hypothesized that in the naturally vasopressin-deficient Brattleboro rat, acute and chronic morphine treatment may lead to reduced HPA axis activity. Rats were treated either with a single dose of morphine (10 mg/kg subcutaneously) and serial blood samples were taken or were treated twice daily with increasing doses of morphine (10-100 mg/kg subcutaneously) for 16 days and animals were killed by decapitation 4 or 16 h after the last injection. Single morphine injection induced a biphasic ACTH and corticosterone elevation with smaller increases in vasopressin-deficient rats. Chronic morphine treatment induced the typical somatic and HPA axis changes of chronic stress; the absence of vasopressin did not prevent these changes. In rats repeatedly treated with morphine plasma, ACTH and corticosterone levels were elevated both 4 and 16 h after the last injection (short and long withdrawal) and the absence of vasopressin attenuated this response. Our data suggest that vasopressin plays a prominent role in morphine treatment and withdrawal-induced acute hormonal changes, but does not affect development of chronic hyperactivity of the HPA axis.

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats.

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.

Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression.

Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.

Impaired histamine- and stress-induced secretion of ACTH and beta-endorphin in vasopressin-deficient Brattleboro rats.

Arginine vasopressin (AVP), corticotropin-releasing hormone (CRH) and catecholamines seem to be involved in the histamine- (HA) and/or stress-induced release of the pro-opiomelanocortin-derived peptides adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END). The AVP component of the regulatory mechanism can be specifically studied in Brattleboro rats which lack AVP. These animals may therefore serve as a useful biological model for investigating the importance of AVP in the ACTH and beta-END response to HA and stress. On this background, we studied the ACTH and beta-END response to HA or restraint stress in conscious, male dizygotic AVP-deficient Brattleboro rats (DI) and compared the hypothalamic content of CRH and catecholamines in these rats with that of nondiabetic isogenic Long-Evans rats (LE). In addition, we studied the hypothalamic AVP content in LE rats after HA infusion or exposure to restraint stress. HA (270 nmol) administered intracerebroventricularly (i.c.v.) or 5 min of restraint stress caused a 6- to 7-fold increase in plasma concentrations of ACTH and beta-END in LE rats but only a 2- to 3-fold increase in DI rats (p < 0.01 vs. LE). The basal hypothalamic content of CRH and catecholamines (epinephrine, norepinephrine, and dopamine) was similar in DI and LE rats. The hypothalamic AVP content in LE rats was unaffected by central HA infusion or restraint stress and was undetectable in DI rats. We conclude that inherited lack of AVP impaired the ACTH and beta-END response to central HA administration as well as to restraint stress, suggesting that AVP is important for the mediation of these responses.

Development of a new strain of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus.

The aim of the present study was to investigate whether the presence of arginine vasopressin (AVP) is necessary for the establishment of high blood pressure in spontaneously hypertensive rats (SHR). For this purpose we crossbred SHR of the stroke-prone substrain (SHRSP) with rats homozygous for hypothalamic diabetes insipidus of the Brattleboro strain (DI) which are unable to synthetize AVP. The successful introduction of the DI gene into the SHRSP strain (SHRDI) was demonstrated by the following observations: In 10-month-old rats, water intake was similarly elevated in SHRDI as in DI rats (137 +/- 6.5 vs 125 +/- 10.5 ml per 24 hours). AVP was undetectable in the plasma, in the hypothalamus, and in the pituitary of SHRDI and DI rats. Urine osmolality and urinary concentration of sodium and potassium were markedly reduced. SHRDI and DI did not adequately concentrate their urine during an 8-hour period of water deprivation, but both strains of rats responded well with a fall in urine output and a rise in urine osmolality to subcutaneous administration of the non-pressor analog of AVP, DDAVP. Mean arterial blood pressure was markedly increased in SHRDI as well as in SHRSP (184 +/- 9.7 vs 197 +/- 5.2 mm Hg). Thus, we have developed a new line of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus. From this finding it is concluded that AVP is not essential for the development and maintenance of spontaneous hypertension of rats.