Significance of the adrenergic system in the regulation of vasopressin secretion in rat neurohypophyseal tissue cultures.

UNLABELLED: The effects of adrenaline (A) and noradrenaline (NA) on vasopressin (VP) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP contents of the supernatant media were determined by radioimmunoassay after a 1 or 2-h incubation. Significantly increased VP levels were detected in the tissue culture media following the administration of A (an alpha+beta(2)-receptor agonist), depending on the dose of A. The VP secretion elevation was totally blocked by the previous administration of phentolamine (an alpha(1)+alpha(2)-receptor antagonist) or corynanthine (an alpha(1)-receptor antagonist). Yohimbine (an alpha(2)-receptor antagonist) did not influence the VP secretion increase induced by A. After the administration of NA (a beta+alpha(1)-receptor agonist), a VP secretion elevation was again detected, but the degree of enhancement proved smaller than that of the VP secretion increase induced by A. Propranolol (a beta(1)+beta(2)-receptor antagonist) before NA administration prevented the VP secretion increase. Atenolol (a beta(1)-receptor antagonist) did not block the VP secretion elevation induced by NA. Corynanthine (an alpha(1)-receptor antagonist) treatment before NA administration reduced the NA-induced VP enhancement, because NA has an alpha(1)-receptor agonist character in addition to its main character (a beta-receptor agonist). Surprisingly, the administration of pindolol (a beta(1)+beta(2)-receptor antagonist) enhanced VP secretion. This contradictory effect can be explained in that pindolol not only acts as a blocker, but also exerts "intrinsic sympathomimetic action" and a strong adrenergic agonist effect. Pindolol before NA administration significantly increased the NA-induced VP elevation. CONCLUSIONS: Mainly the alpha(1)- and beta(2)-adrenergic receptors are involved in the A- or NA-induced increase of VP secretion in isolated NH tissue cultures. The results indicate that VP release is influenced directly by the adrenergic system, and the adrenergic control of VP secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Inhibitory effect of vasopressin receptor antagonist OPC-31260 on experimental brain oedema induced by global cerebral ischaemia.

The effects of the non-peptide vasopressin V(2) receptor antagonist 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by general cerebral hypoxia were studied in rats. The general cerebral hypoxia was produced by bilateral common carotid ligation in Sprague-Dawley rats of the CFY strain. By 6 h after the ligation, half of the rats had died, but the survival rate was significantly higher following OPC-31260 administration. Electron microscopic examinations revealed typical ischaemic changes after the carotid ligation. The carotid ligation increased the brain contents of water and Na(+) and enhanced the plasma vasopressin level. The increased brain water and Na(+) accumulation was prevented by OPC-31260 administration, but the plasma vasopressin level was further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of the disturbances in brain water and electrolyte balance in response to general cerebral hypoxia. The carotid ligation-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on the renal vasopressin V(2) receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

Histamine-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue cultures.

The effects of histamine (HA) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay (RIA) after a 1 or 2-h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following HA administration, depending on the HA dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the HA antagonist mepyramine (MEP, an H1 receptor antagonist) or cimetidine (CIM, an H2 receptor antagonist). Thioperamide (TPE, an H3-H4 receptor antagonist) did not influence the VP or OT secretion increase induced by HA. The application of MEP, CIM or TPE after HA administration proved ineffective. The H1 and H2 receptors are mainly involved in the HA-induced increase of both VP and OT secretion in isolated NH tissue cultures. The results indicate that NH hormone release is influenced directly by the histaminergic system, and the histaminergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Five different adenomas derived from the rat adenohypophysis: immunocytochemical and ultrastructural study.

With the use of electron microscopic morphology and immunochemistry, 5 tumors were studied: a spontaneous prolactin-producing adenoma (LEP rats); an estrogen-induced intrasellar tumor (R-Amsterdam rats); and 3 transplanted tumors, MtT.W10 and MtT.W5 (WF rats) and MtT.F4 (F344 rats). All tumors were derived from rat adenohypophysis and are known to secrete prolactin, growth hormone, or adrenocorticotropic hormone. The spontaneous tumor consisted of a uniform population of cells containing only immunoreactive prolactin. In the estrogen-induced tumor, prolactin and growth hormone were localized in separate cell types with the use of the immunoperoxidase technique. In the MtT.W10 tumor, both immunoreactive prolactin and growth hormone were observed in the same cell and in separate cell types. In the MtT.F4 and MtT.W5 tumors, one cell type was identified that was characterized by lack of morphologic differentiation, reduced secretory granule number, and inconclusive immunopositivity.

Serotonin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue culture.

The effects of serotonin (5-hydroxytryptamine; 5-HT) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay after a 1 or 2 h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following 5-HT administration, depending on the 5-HT dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the 5-HT antagonist ketanserin or metergoline. WAY-100635 did not influence the increased VP secretion induced by 5-HT, but the elevated OT production was prevented by WAY-100635 before 5-HT administration. The application of WAY-100635, ketanserin or metergoline, after 5-HT administration proved ineffective. The results indicate that NH hormone release is influenced directly by the serotonergic system. The serotonergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.

Biological half-life and organ distribution of [3H]1-deamino-8-D-arginine-vasopressin in the rat.

The biological half-life of synthetic, radiochemically pure, biologically active [3H]1-deamino-8-D-arginine-vasopressin (dDAVP) in rats was found to be 5.33 +/- 0.28 (S.E.M.) min in the initial, transitional, fast phase and 56.28 +/- 3.27 min in the second, slow phase. The substance accumulated to the greatest extent in the kidney and small intestine and only slightly in the adenohypophysis. The results have suggested that the extended biological half-life may play a role in the more marked and longer antidiuretic effect of dDAVP. The explanation of the poor accumulation in the adenohypophysis may be that dDAVP does not possess an effect similar to that of corticotrophin releasing factor.

Biological half-life and organ distribution of [3H]8-arginine-vasopressin in the rat.

The biological half-life of synthetic, radiochemically pure, biologically active [3H]8-arginine-vasopressin ([3H]AVP), the distribution of radioactivity among the organs and the in-vivo metabolism of the hormone were studied in the rat. The half-life calculated from the [3H]AVP radioactivities isolated from the blood was found to be 1.74 +/- 0.22 (S.D.) min in the fast phase, and 16.98 +/- 1.01 min in the slow phase. The half-lives of total radioactivity were longer in both phases. The radioactivity accumulated to the greatest extents in the adenohypophysis and small intestine. The radioactive substance was accumulated more by the kidney than by the liver, but the hormone underwent inactivation more quickly in the liver.

Mechanism of restoration of ACTH release in rats with long-term lesions of the paraventricular nuclei.

The effects of lesions in the paraventricular nucleus (PVN) on the adrenocortical response to ether stress were investigated in neurohypophysectomized and intact rats. During the first 4 days after placement of lesions in the PVN, the corticosterone response to ether stress was almost completely inhibited. It then gradually increased and, within 4-6 weeks of surgery, was restored to about 60% of that in sham-operated rats. Basal plasma concentrations of corticosterone were low in rats after placement of lesions in the PVN and/or after neurointermediate lobectomy (NILX). Corticosterone responses to ether stress were similar in groups submitted to PVN lesions and/or NILX, and lower than those in the appropriate sham-operated groups. In all lesioned groups, plasma ACTH concentrations after a combination of stressors (ether plus laparotomy) were also lower than those in the sham-operated groups. Six weeks after lesioning of the PVN, immunoreactive rat corticotrophin-releasing factor-41 (rCRF-41) concentrations in stalk-median eminence (SME) extract fell to about 5% of that in sham-operated rats, while immunoreactive arginine vasopressin (AVP) concentrations did not change. Immunohistochemistry revealed a substantial decrease in rCRF-41 immunostaining of the median eminence 6 weeks after lesioning of the PVN, though randomly located clusters of stained terminals were still seen in the whole rostro-caudal extent of the median eminence. A mixture containing synthetic rCRF-41 and AVP, in proportions similar to those in SME extracts from sham-operated rats, caused significantly less release of ACTH from anterior pituitary cell cultures than did SME extracts from sham-operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lysine-vasopressin and 1-deamino-8-D-arginine-vasopressin on memory in healthy individuals and diabetes insipidus patients.

Central diabetes insipidus (DI) patients showed impairments in short- and long-term memory functions, but not in attention and concentration, as compared to healthy individuals. A single i.m. injection or sub-chronic intranasal administration of either lysine-vasopressin (LVP) or 1-deamino-8-D-arginine-vasopressin (DDAVP) normalized the disturbed memory functions in DI patients. These peptides also improved memory functions in healthy individuals.

Effect of a vasopressin antagonist d(CH2)5Tyr(Met)AVP on the development of renal vasospasm induced by estrin plus vasopressin administration in rats.

The authors studied rats pretreated with estrin acetate to determine the renal circulation changes caused by vasopressin and how these changes are influenced by the pressor effect of an antagonist of vasopressin d(CH2)5Tyr(MET)AVP. Abdominal angiography was performed with contrast material administered via a catheter introduced through the common carotid artery up to the aortic arch. After vasopressin administration, a marked spasm occurred in the larger renal arteries, the arteriovenous time increased, and the parenchymal filling became defective. Renal circulation remained undisturbed if the vasopressin antagonist was administered simultaneously. The results suggest that the vasopressin antagonist prevents renal vasospasm after vasopressin administration in rats pretreated with estrin.

Serioangiographic study of renal cortical necrosis induced by administration of estrin and vasopressin in rats.

We report a serioangiographic method in rats which permits assessment of the course and dimensions of the renal arteries, the durations of the arterial and venous phases, and the intensity and uniformity of the renal parenchymal filling. The procedure was employed to study the mechanism by which administration of vasopressin to rats pretreated with estrin leads to renal cortical necrosis. The pathogenetic significance of the spasm localized on the larger renal arteries was proved directly; the possible role of the arteriovenous shunt in the development of the renal ischemia was excluded.

Biological half-lives and organ distribution of tritiated 8-lysine-vasopressin and 1-deamino-8-D-arginine-vasopressin in Brattleboro rats.

The biological half-lives and organ distribution of tritiated 8-lysine-vasopressin and 1-deamino-8-D-arginine-vasopressin were determined in R-Amsterdam rats and in homozygous and heterozygous Brattleboro rats with hereditary central diabetes insipidus. It was found that the biological half-lives of [3H]LVP and [3H]dDAVP in the Brattleboro rats did not differ significantly from that found in the control R-Amsterdam rats. The half-life of [3H]dDAVP proved longer than that of [3H]LVP in all three groups of animals. In the case of [3H]LVP the highest radioactivities were observed in the neurohypophyses, adenohypophyses, and kidneys of both the R-Amsterdam and Brattleboro rats. The accumulation of tritiated material was higher in the small intestine of the Brattleboro rats than in that of the R-Amsterdam animals. In all three groups of rats, [3H]dDAVP was accumulated to the greatest extent in the kidney and the small intestine. The kidney and small intestine contained less radioactivity in homozygous Brattleboro rats than in the controls. There was only a slight radioactivity accumulation in the adenohypophysis and neurohypophysis. From the results it was concluded that the decrease in the rate of enzymatic decomposition may play a role in the increased duration of antidiuretic action of dDAVP. The results have led to the conclusion that the accelerated elimination of vasopressin and its pathologic organ accumulation are probably not involved in the water metabolism disturbance of Brattleboro rats with hereditary diabetes insipidus.

Evidence that the effects of arginine-8-vasopressin (AVP) on pituitary corticotropin (ACTH) release are mediated by a novel type of receptor.

Ovine corticotropin releasing factor (oCRF-41) and AVP act synergistically to stimulate pituitary ACTH secretion. In the present study we have investigated whether the effect of AVP, either in the presence or in the absence of oCRF-41 (0.5 nmol/l), could be blocked by V1 (pressor)-antagonists. Furthermore, oxytocin, and [1-deamino,8-D-arginine] vasopressin (dDAVP) were tested for their ability to release ACTH. All experiments were carried out in vitro, using segments of rat anterior pituitary glands. The V1-antagonist [1-deamino,penicillamine(o-methyl-tyrosine)]AVP inhibited ACTH release induced by AVP or AVP + oCRF-41. However, it also had some agonistic activity which was more pronounced in the presence of oCRF-41. An equally potent V1-antagonist, [1-beta-mercapto-beta, beta-cyclopentamethyleneproprionic acid (o-methyl-tyrosine)]AVP, failed to inhibit AVP-stimulated ACTH secretion, and also had weak agonist potency. The relatively selective V2 (antidiuretic)-agonist dDAVP was 20-30 fold less potent than AVP. Oxytocin, a weak V1- and V2-agonist was only 4-8 fold less potent than AVP. These data are compatible with the suggestion that AVP receptors on pituitary corticotrope cells are neither classical V1- nor V2-receptors.

Gastric mucosal endogenous prostacyclin levels are different in Brattleboro rats compared with Wistar strain.

Homozygous Brattleboro rats were investigated and compared to normal (physiological) Wistar strain rats regarding their gastric mucosal endogenous prostacyclin (PG-I(2)) level. It seems that the Brattleboro animals have a significantly lower level of this important protective material. Wistar rats having an artificial pituitary stalk lesion (which is the artificial equivalent of homozygous Brattleboro animals) showed no differences in endogenous mucosal prostacyclin level compared to normal Wistar rats. Therefore, we concluded that this hitherto unknown property of the homozygous Brattleboro rats is genetically determined.

Vasopressin deficiency decreases the frequency of gastroduodenal ulceration in humans.

Vasopressin is a stress hormone released from the posterior pituitary. In humans suffering from central diabetes insipidus, this release of vasopressin is diminished. It was shown previously that the congenitally vasopressin-deficient Brattleboro homozygous rat is less sensitive to various ulcerogenic stimuli. In this study, we investigated the incidence of gastroduodenal ulceration in vasopressin deficient patients. Data on patients aged 20-70, hospitalized in Hungary between 1992 and 1995 were compared with those on the total population in this age group (6,681,020 in 1994). Subjects with central diabetes insipidus were selected separately (815 cases). Gastroduodenal ulceration was compared in subjects with an intact vasopressin release and vasopressin-deficient patients. The frequencies of gastroduodenal ulceration were also examined separately in male and female subjects. In the total population, the frequency of gastroduodenal ulceration was lower in vasopressin-deficient cases (2.22% versus 0.61%; P < 0.005). Among normal-vasopressin subjects, males have a higher risk of gastroduodenal ulceration than females (3.04% versus 1.46%, respectively; P < 0.001). Among vasopressin-deficient subjects, a similar male:female ratio was observed, but it was not significant (P = 0.36). In comparison to the normal-vasopressin population, the incidence of gastroduodenal ulceration was reduced among vasopressin-deficient males and females by 77% (P < 0.01) and by 82% (P < 0.05), respectively. In conclusion, endogenous vasopressin has a significant harmful action towards the human gastroduodenal mucosa. Peptide and non-peptide vasopressin receptor antagonists might have a potential therapeutic benefit in the treatment (as an adjuvant) and prevention of gastroduodenal ulceration.

Detrimental effects of oestradiol on cysteamine-induced gastroduodenal ulceration in the female rat.

The actions of the female sex steroid, oestradiol on cysteamine-induced mucosal ulceration has been evaluated in female Wistar rats. Administration of cysteamine (400 mg x kg(-1), s.c.) provoked macroscopic gastroduodenal mucosal injury (assessed planimetrically) and an increase in microvascular permeability (assessed by the extravasation of radiolabeled albumin) in the stomach and duodenum, determined 24 h later. Ovariectomy (2 weeks before cysteamine) reduced gastroduodenal macroscopic injury, and albumin extravasation following cysteamine challenge. Administration of oestradiol (1-5 mg x kg(-1), as an i.m. depot 1 week before cysteamine) dose-dependently augmented gastric and duodenal macroscopic mucosal lesions and microvascular permeability provoked by cysteamine. These findings indicate that oestradiol can exacerbate gastroduodenal ulceration and microvascular injury.

Effects of dopamine and dopamine-active compounds on oxytocin and vasopressin production in rat neurohypophyseal tissue cultures.

The effects of dopamine (DA) or DA-active drugs on the synthesis of neurohypophyseal (NH) hormones were studied in 13-14 day cultures of isolated NH tissue from rats. The following DA-active compounds were used (10(-6) M in each medium): DA, apomorphine (APM), Pro-Lys-Gly (PLG), butaclamol (B), haloperidol (HP), chlorpromazine (CPZ) and sulpiride (SP). The oxytocin (OT) and vasopressin (VP) contents of the condensed media were determined by RIA after a 1 or 2 h incubation. Significantly increased contents of OT and VP were detected in the tissue culture media following DA, APM or PLG administration. This elevation of NH hormone production could be blocked by previous administration of B or the DA receptor antagonists HP, CPZ or SP. The application of B after DA agonists proved ineffective. The results indicate that NH hormone production can be directly influenced by the DA-ergic system. The DA-ergic control of NH hormone secretion in rats can occur independently of the hypothalamus, at the level of the posterior pituitary.

Inhibitory effect of galanin on dopamine-induced enhanced vasopressin secretion in rat neurohypophyseal tissue cultures.

The effect of galanin (GAL) on vasopressin (VP) secretion was studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP content of the supernatant was determined by radioimmunoassay (RIA) after a 1- or 2-h incubation. A significantly decreased content of VP was detected following the administration of 10(-6)-10(-9) M doses of GAL. Dopamine (DA) and the DA-active drugs apomorphine (APM) and Pro-Lys-Gly (PLG) (10(-6) M in each medium) increased the VP level of NH tissue cultures. This VP concentration elevation could be blocked by the administration of GAL together with DA, APM or PLG. The DA-blocking effect of GAL was prevented by previous treatment with the GAL receptor antagonist galantid (M15). The results indicate that VP release is directly influenced by the GAL-ergic system. The GAL-ergic control of VP secretion from NH tissue in rats can occur independently of the hypothalamus, at the level of the posterior pituitary.

Inhibitory effect of galanin on dopamine induced increased oxytocin secretion in rat neurohypophyseal tissue cultures.

The regulation of oxytocin (OT) release by galanin (GAL) at the neurohypophyseal (NH) nerve terminal is not adequately understood. The effect of GAL on the secretion of OT was studied in 13- to 14-day cultures of isolated rat NH tissue. By this time, the hormone content of the medium had become constant. The OT content of the supernatant medium was determined by RIA after a 1- or 2-h incubation. A significantly decreased content of OT was found following incubation with 10(-6)-10(-8) M doses of GAL. Dopamine (DA) and the DA-active drugs apomorphine (APM) and Pro-Lys-Gly (PLG) (10(-6) M in each medium) increased the OT synthesis of NH tissue cultures. This elevation of OT secretion could be blocked by the administration of GAL together with DA, APM or PLG. The DA-blocking effect of GAL was prevented by previous treatment with the GAL receptor antagonist galantid (M15). The results indicate that OT release from the NH is directly influenced by the GAL-ergic system. The GAL-ergic control of OT secretion from NH tissue in rats can occur at the level of the posterior pituitary.

Presence of chromatographically identified oxytocin in human sensory ganglia.

Oxytocin-like immunoreactivity (IR-OXT) was detected in extracts of human spinal L5 and Gasserian ganglia by a radioimmunoassay (RIA) specific to oxytocin (OXT) and was identified by high-performance liquid chromatography (HPLC). One of the two immunoreactive peaks obtained on HPLC was found to elute at the same position as the OXT standard. The results reveal the presence of chromatographically identified OXT immunoreactivity in human sensory ganglia.