F. László

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.

Cerebral oedema after subarachnoid haemorrhage. Pathogenetic significance of vasopressin

SummaryThe authors report the frequency, characteristic clinical symptoms, laboratory alterations and diagnostic criteria of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after subarachnoid haemorrhage.The data on 290 patients with subarachnoid haemorrhage (SAH) during a period of years at the Division of Neurosurgery, University Medical School, Szeged, are analysed. Twenty-seven (9.3%) patients developed SIADH. Thirteen (4.5%) patients had severe and 14 (4.8%) had mild SIADH. The problems of the treatment are discussed in detail and the different therapeutic methods are listed: Nad infusion, water withdrawal and administration of Dilantin, diuretics, mineralocorticosteroids, lithium and demeclocycline. The undesirable side-effects observed accompanying various therapeutic regimen are analysed. The introduction of V2 antagonists into clinical practice appears to be a most perspective procedure.For study of the pathogenesis of SIADH following SAH, the possibility of treatment with V2 antagonists on an experimental model of SAH in rat was created. A significant water retention and increases in brain water and sodium content were observed in rats with SAH. Plasma AVP levels were also elevated after SAH. AVP plays an important role in the development of antidiuresis following water loading and disturbance of the brain water and electrolyte balance after SAH. Water retention and the higher brain water and sodium accumulation could be totally prevented by administration of a V2 antagonist. These results demonstrate that cerebral oedema generated by artificial cerebral bleeding in rats is significantly reduced following the administration of a highly specific V2 antagonist, suggesting a new approach to the treatment of SIADH.

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.

Aggressive role of vasopressin in development of different gastric lesions in rats

The effects of endogenous or exogenous vasopressin in models of gastric mucosal injury with a different pathophysiology (ethanol, indomethacin, reserpine, cold-restraint stress and haemorrhagic shock-induced lesions) were investigated in rats. [Mca1,TyrMe2,Arg8]vasopressin, a vasopressin pressor (V1) receptor antagonist, was found to reduce dose dependently the extent of the lesions in all models, and to protect the deeper layer of the mucosa (assessed by histology). Endogenous vasopressin deficiency, as in Brattleboro homozygous rats, had a similar effect. [Lys8]Vasopressin injected exogenously aggravated all types of lesions in normal rats. Circulating vasopressin levels were increased by ethanol, reserpine, cold-restraint stress and haemorrhagic shock, but not by indomethacin, whereas the intramucosal vasopressin content was found to be elevated in all models. Additionally, specific binding sites for vasopressin were shown on the blood vessels of the gastric mucosa (assessed by autoradiography). It is concluded that vasopressin plays a significant aggressive role in the generation of these types of lesions.

Endogenous vasopressin increases acute endotoxin shock-provoked gastrointestinal mucosal injury in the rat.

Administration of a low dose of endotoxin (from Escherichia coli, 3 mg kg(-1), i.v.), which does not affect vascular permeability or blood pressure over 1 h, leads to the release of endogenous vasopressin and damage to the mucosal microvasculature. Thus, endogenous vasopressin could be involved in septic shock. In the present study, we investigated the role of endogenous vasopressin in gastrointestinal mucosal injury induced by acute endotoxin shock, which was generated in rats by administering a high dose of E. coli endotoxin (50 mg kg(-1), i.v.). Tissues were removed 15 min after endotoxin. The vasopressin V1 receptor antagonist, d[CH2]5Tyr[Me]arginine-vasopressin (0.2-1 microg kg(-1), i.v.), was injected 10 min before endotoxin. Monastral blue (30 mg kg(-1), i.v.), which stains damaged vasculature, was injected 10 min before autopsy. Endotoxin reduced systemic arterial blood pressure (from 115+/-5 to 42+/-4 mmHg), generated macroscopic and microvascular injury, and elevated plasma vasopressin levels (from 3.4+/-0.2 to 178+/-16 pg ml(-1)). The vasopressin V1 receptor antagonist reduced this macroscopic injury, and in the vasopressin-deficient Brattleboro rat a similar reduction of gastrointestinal mucosal damage was found. Substantial decreases in endotoxin-induced microvascular damage were observed in each tissue, e.g., the gastric Monastral blue staining was reduced by 47+/-3% and 96+/-3% (P < 0.01) after vasopressin V1 receptor antagonist treatment and in Brattleboro rats, respectively. Vasopressin, acting through its V1 receptors, thus appears to be involved in acute endotoxin shock-provoked gastrointestinal injury.

Vasopressin receptor antagonist OPC-31260 prevents cerebral oedema after subarachnoid haemorrhage

The effects of the non-peptide vasopressin V2 receptor antagonist, 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrah ydro-1 H-benzazepine hydrochloride (OPC-31260) on the cerebral oedema induced by subarachnoid haemorrhage were studied in rats. Subarachnoid haemorrhage induced significant water retention after water loading, increased the brain content of water and Na+ and increased plasma vasopressin levels. The water retention and brain water and Na+ accumulation were prevented by OPC-31260 administration, but the plasma vasopressin levels were further enhanced by OPC-31260. These results demonstrate the important role of vasopressin in the development of antidiuresis and disturbances in brain water and electrolyte balance in response to subarachnoid haemorrhage. The subarachnoid haemorrhage-induced cerebral oedema was significantly reduced following oral OPC-31260 administration. The protective mechanism exerted by OPC-31260 stems from its influence on renal tubular function: it blocks the renal vasopressin V2 receptors. These observations might suggest a new, effective approach to the treatment of subarachnoid haemorrhage-induced cerebral oedema in humans.

Hereditary diabetes insipidus in rats: Altered cerebral indolamine and catecholamine metabolism

Compared to heterozygous Brattleboro animals, homozygous (diabetes insipidus) rats exhibited higher steady-state levels of serotonin in the mesencephalon, septum and striatum. These differences disappeared upon the administration of pargyline, suggesting accumulation of serotonin. The norepinephrine level was higher in the mesencephalon, while the disappearance rate (alpha-met hyl-p-tyrosine) was accelerated in the septum and decreased in the hypothalamus. The lower striatal dopamine level was associated with a decreased disappearance rate. The data suggest that the altered monoamine metabolism might be associated with the known endocrine and behavioral disturbances of the homozygous rats.

IDENTIFICATION OF OXYTOCIN AND VASOPRESSIN FROM NEUROHYPOPHYSEAL CELL CULTURE

Our observation that dispersed cultures of neurohypophysis obtained from adult rats are capable of synthesizing and releasing oxytocin and vasopressin is unexpected, because in whole animals these hormones are known only to be stored, not to be produced in the posterior lobe of the pituitary. The hormone content of cell culture medium was elevated from 0 to 129 +/- 14 pg/mg protein for oxytocin and from 0 to 42 +/- 4 pg/mg protein for vasopressin during two weeks as determined by specific radioimmunoassay. By molecular mass and structure determination (tandem mass spectrometry) we have proved that the supernatant of the cell cultures contains not only immunologically but mass spectrometrically identified neurohypophyseal hormones.

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

SummaryThe effects of the non-peptide vasopressin V2 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 V2 receptors. These observations might suggest an effective approach to the treatment of global hypoxia-induced cerebral oedema in humans.

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.