Octreotide-induced drinking, vasopressin, and pressure responses: role of central angiotensin and ACh.

The involvement of central angiotensinergic and cholinergic mechanisms in the effects of the intracerebroventricularly injected somatostatin analog octreotide (Oct) on drinking, blood pressure, and vasopressin secretion in the rat was investigated. Intracerebroventricular Oct elicited prompt drinking lasting for 10 min. Water consumption depended on the dose of Oct (0.01, 0.1, and 0. 4 microgram). The drinking response to Oct was inhibited by pretreatments with the intracerebroventricularly injected angiotensin-converting enzyme inhibitor captopril, the AT(1)/AT(2) angiotensin receptor antagonist saralasin, the selective AT(1) receptor antagonist losartan, or the muscarinic cholinergic receptor antagonist atropine. The dipsogenic effect of Oct was not altered by prior subcutaneous injection of naloxone. Oct stimulated vasopressin secretion and enhanced blood pressure. These responses were also blocked by pretreatments with captopril or atropine. Previous reports indicate that the central angiotensinergic and cholinergic mechanisms stimulate drinking and vasopressin secretion independently. We suggest that somatostatin acting on sst2 or sst5 receptors modulates central angiotensinergic and cholinergic mechanisms involved in the regulation of fluid balance.

[Current diagnostic method, prognosis estimation and therapy of papillary thyroid cancer: recommendations of the medical universities and the National Oncologic Institute of Budapest]. / A papillaris pajzsmirigy-carcinoma korszerü kivizsgálása, prognózisbecslése és kezelése: az orvostudományi egyetemek és az Országos Onkológiai Intézet ajánlása.

Physical examination, cervical ultrasonography (US) and aspiration cytology are the mainstays of the preoperative diagnostics of papillary thyroid carcinoma. For the staging of suspected malignant cases, cervical and mediastinal CT (MRI for inconclusive results) is indicated before any surgery. The end-result of primary treatment is assessed by total-body iodine scintigraphy and the serum human thyroglobulin (hTG) level. For long-term follow-up, physical examination and the serum hTG level are the most reliable tools (6-monthly), supplemented by cervical US and chest X-ray (yearly), and total-body iodine scintigraphy (2-yearly). If these furnish positive results, further examinations may be indicated. In suspected relapses of hTG non-producing and iodine non-accumulating papillary carcinomas, 201thallium chloride or 99mTc-sesta-MIBI (methoxy-isobutyl-isonitrile) scintigraphy, and positron emission tomography with 18fluoro-deoxyglucose or 11C-methionine may be of help. For estimation of the prognosis (cause-specific survival) of the patients, the MACIS score system of the Mayo Clinic is widely accepted, the patients being divided into low-risk and intermediate/high-risk categories. The recommended standard surgical intervention is near-total thyroidectomy (2-4 g residual glandular tissue left at the upper pole of the less-involved lobe), with a central cervical lymph node dissection for diagnostic purposes. In cases of lymph node dissemination, dissection (radical, modified radical, selective or microdissection) of any of the involved compartments (central, right or left cervical, or upper mediastinal) is indicated for therapeutic reasons, the method of which is depending on the extent of the metastatic involvement. Following adequate surgical intervention, no adjuvant radioiodine therapy is indicated for low-risk cases with a tumour of less than 1 cm diameter. For other low-risk or intermediate/high-risk patients, radioiodine ablation (R0N0M0) or a therapeutic radioiodine dosage (R2N1M1) is indicated. In cases at high-risk of local/regional relapse and in radioiodine non-accumulating tumorous cases, external radiotherapy may be applied. Thyroid hormone medication in a TSH suppressive dose is indicated during the first 5 postsurgical years: the goal is to achieve a TSH level below 0.1 (determined by a 3rd generation assay). If no relapse occurs or the case is a low-risk one, following the 5 years, it is enough to maintain the TSH level in a subnormal range (0.1-0.3).

Neurohypophysial hormone secretion in hyperprolactinaemic women.

Prolactin (PRL) has been reported to promote antidiuresis and increase intestinal water-electrolyte absorption, whereas osmolar changes have been shown to influence PRL secretion. However, the mechanisms of action of PRL on the salt-water balance remain unclarified. The present clinical study targeted the effects of hyperprolactinaemia on the secretion of arginine-8-vasopressin (AVP), oxytocin (OXT) and cortisol. Plasma AVP and OXT were measured by radioimmunoassay, and cortisol by fluorimetry. In healthy women (21-39 y, n=6), an oral water load (OWL, 20 ml/bw) significantly suppressed the plasma levels of AVP, OXT and cortisol, and the PRL level too tended to decrease. In hyperprolactinaemic females (22-41 y, n=6, three with pituitary adenomas), water retention was registered following an OWL, together with paradoxical AVP and OXT level increases, whereas the cortisol response remained normal, and the PRL level did not change at all. Histamine (0.5 mg sc) stimulated the release of AVP, OXT and cortisol in the control and hyperprolactinaemic groups alike. These data suggest that alterations in AVP and OXT hypersecretion may contribute to the water retention in hyperprolactinaemia.

[Effect of somatostatin-octreotide on secretion of adrenocorticotropin, cortisol and neuro-hypophyseal hormones in acromegaly]. / Szomatosztatin-oktreotid hatása az adrenokortikotrop hormon, kortizol és a neurohypophysis hormonok elválasztására acromegaliában.

The present work was aimed at studying the combined effects of somatostatin and corticotropin releasing hormone on the activities of the pituitary-adrenocortical axis and neurohypophysis. Patients with active acromegaly were intravenously injected with a 100 micrograms human corticotropin releasing hormone bolus before and after a 3-month subcutaneous treatment with somatostatin-octreotide (SMS 201 995; Sandostatin; 200 micrograms t. i. d.). When the Sandostatin effect was investigated, corticotropin releasing hormone test was started 2 hrs after its first daily dose. Peripheral venous blood samples were taken before and 20, 60, 90 and 120 min after the corticotropin releasing hormone load. Plasma corticotropin, arginine-8-vasopressin and oxytocin were measured by radioimmunoassay, and serum cortisol by fluorimetry. In healthy subjects, corticotropin releasing hormone stimulus elicited increases of plasma corticotropin, serum cortisol, plasma arginine-8-vasopressin and oxytocin levels by 186, 41, 178 and 58 per cent, respectively. Untreated acromegalics exhibited missing arginine-8-vasopressin, blunted corticotropin, and normal oxytocin and cortisol responses. Sandostatin therapy improved the arginine-8-vasopressin reaction, suppressed the basal levels of corticotropin and cortisol with the maintenance of cortisol stimulability; the peak-reaction of corticotropin became normal in two patients, however, with a shortened duration of response. Diuresis of the patients increased under the treatment. Sandostatin markedly alleviated the clinical symptoms and suppressed the growth hormone secretion, but did not influence the size of the pituitary adenomas. Among other factors, the alterations of growth hormone and cortisol may be hypothesized to take part in the changes of the corticotroph and neurohypophysial functions.

Changes in rat sleep after single and repeated injections of the long-acting somatostatin analog octreotide.

Somnogenic activity is attributed to both growth hormone (GH) and GH-releasing hormone (GHRH). The aim of our experiments was to study sleep after suppression of the somatotropic axis by means of administration of a long-lasting somatostatin analog, octreotide. Rats received subcutaneous injections of physiological saline (baseline), octreotide (1, 10, and 200 microg/kg), or a control solution just before light onset, and sleep-wake activity and cortical brain temperature were recorded for 23 h. Each dose of octreotide slightly promoted rapid eye movement sleep (REMS) during the 12-h light period. Non-REM sleep (NREMS) was strongly suppressed for 1 h in response to 10 and 200 microg/kg octreotide. This was followed by slight increases in NREMS time and significant enhancements in electroencephalogram slow-wave activity during NREMS after 200 microg/kg octreotide. The octreotide-induced inhibition of the somatotropic axis, as determined by plasma GH levels, vanished by the time sleep increased. Another group of rats received 10 microg/kg octreotide twice a day for 5 days. This treatment elicited persistent decreases in both NREMS time and NREMS intensity. The results support the previously reported REMS-promoting activity of somatostatin in rats. The decreases in sleep after repeated injections of octreotide are attributed to a withdrawal of the normal sleep-promoting activity of GH. The role of GHRH-GH in octreotide-induced acute suppression of NREMS is currently not clear. Other mechanisms, such as mimicking central transmitter functions of somatostatin by octreotide, should also be considered.

[Repeated serious water intoxication in an aged patient. (Data on the relationship between the inappropriate antidiuretic hormone syndrome and the atrial natriuretic factor)]. / Ismétlödö súlyo vízmérgezések egy idös betegben (Adatok az "inappropriate antidiuretic hormone" syndroma és az atrialis natriureticus factor kapcsolatához).

An old women was in an 8-year-period 9 times admitted to the hospital because of severe mental disturbances. The average serum sodium concentration was 126.25 +/- 2.43 mmol/l at the admissions; it increased to 139.44 +/- 1.40 mmol/l after intravenous infusion of hypertonic solutions accompanied with the disappearance of the mental disturbances. The patient was usually chronically hyponatremic due to the increased water intake and the insufficient water excretion. The latter was induced by the augmented vasopressin levels. The remarkable feature of the syndrome of inappropriate antidiuretic hormone secretion was its association with lowered blood level of atrial natriuretic factor accompanied by sodium, and volume depletion. Discontinuation of the exaggerated water intake resulted in the elimination of the permanent hyponatremia; no episode of water intoxication occurred during the last 3 and 1/2 years.

Specific radioimmunoassay of oxytocin in rat plasma.

Sensitive, specific and reproducible radioimmunoassay (RIA) was developed for the measurement of oxytocin (OXT) in rat blood plasma after various extraction methods. The assay is based on an antiserum raised against OXT in rabbit. The sensitivity, affinity constant, and cross-reactivity of the antiserum were determined. The 125I-labelled OXT for RIA was produced by chloramine-T method and purified with high pressure liquid chromatography (HPLC). Two extraction procedures were employed: 1. adsorption to an artificial silicate, Lichroprep Si 60 (Merck); 2. immunoextraction of the hormone applying a magnetic bearer covered with purified antibodies against OXT. The specificity of the extraction methods was characterized in comparative HPLC/RIA studies of specimens extracted from blood plasma in different ways. The basal level of the peptide measured after the extraction with thermally activated Lichroprep Si 60 or after the immunoextraction method was found to be 9.6 +/- 2.3 pg/ml (mean +/- S.E.) and 15.3 +/- 0.9 pg/ml (mean +/- S.E.), respectively. Various well known factors (ether exposure, hyperosmotic stress and suckling) appeared to be potent peripheral stimuli of OXT release, and thus indicated the suitability of the RIA method for the measurement of OXT in blood plasma.

The role of central corticoliberin in the hyperosmosis-induced secretion of neurohypophysial hormones and corticosterone in the rat.

Although synthetic corticotropin-releasing hormone (CRH) is known to influence the secretion of the neurohypophysial hormones, the role of endogenous CRH in the rat brain is still unclear in this respect. Accordingly, experiments were scheduled to study the effects of intracerebroventricularly (i.c.v.) administered CRH-antiserum (AS) on the hyperosmosis-induced secretion of arginine-8-vasopressin (AVP), oxytocin (OXT) and corticosterone in Wistar male rats. A 2 microliters CRH-AS injection was given, and repeated 24 h later, 30 min prior to intraperitoneal administration of hypertonic saline (HS; 2.5% NaCl, 2 ml/100 g body weight) followed by decapitation in 15 min. Plasma AVP and OXT were measured by radioimmunoassay and corticosterone by fluorimetry. HS increased the levels of AVP, OXT and corticosterone. CRH-AS did not change the plasma concentrations of these hormones in 0.9% NaCl-treated animals. CRH-AS pretreatment prevented the corticosterone-releasing action of HS, and significantly moderated the HS-induced AVP and OXT increase. These findings suggest that the central CRH system may participate in the regulation of corticosterone and neurohypophysial hormone secretion evoked by acute osmotic challenge.

Pharmacokinetics of DGAVP in plasma following intranasal and oral administration to healthy subjects.

A pharmacokinetic study was carried out to assess the bioavailability of desglycinamide-[Arg8]vasopressin (DGAVP, Org 5667). DGAVP (2 mg) was administered both intranasally and orally to healthy subjects with a treatment interval of 1 week. Blood samples were taken regularly between 15 min before and 210 min after administration and were assayed for DGAVP by radioimmunoassay. In all subjects endogenous vasopressin (AVP) levels were detectable. Peak levels of DGAVP occurred at 15 min after both treatments. The mean absorption half-life was 8.7 and 7.3 min and the mean elimination half-life was 38 and 34.6 min for the intranasal and oral route of administration, respectively. The bioavailability of orally administered DGAVP was low compared with the intranasally administered drug; the relative bioavailability of oral/nasal administration was 0.7%. The results indicate that DGAVP is absorbed rapidly after both oral and intranasal administration, but the intranasal route of administration of DGAVP is 100 times more effective in increasing plasma DGAVP levels.

The role of central corticoliberin in the ether stress-induced secretion of neurohypophyseal hormones and corticosterone in the rat.

As corticotropin-releasing factor (CRF) and oxytocin (OXT) are released in response to various stressors and a role of CRF in stress-induced OXT secretion has been proposed by previous authors, the present experiments were scheduled to investigate the participation of the brain CRF system in the stress-evoked release of OXT, arginine-8-vasopressin (AVP) and corticosterone. CRF-antiserum (AS) was given into the lateral ventricle of the brain of Wistar male rats, and 24 h later, the injection was repeated 30 min prior to ether stress followed by decapitation in 5 min. Plasma OXT and AVP were measured by radioimmunoassay and corticosterone by fluorimetry. Ether stress increased the levels of corticosterone and OXT, but not that of AVP. CRF-AS alone did not change the secretion of these hormones. CRF-AS pretreatment blocked the corticosterone-releasing action of ether stress, whereas it exerted no influence on the stress-induced OXT secretion into the circulation. There was no effect of a combined application of CRF-AS and stress on the plasma AVP level. These results suggest that the central CRF system is involved in the ether stress-elicited corticosterone response, however CRF is unlikely to be connected with the regulation of OXT secretion under these experimental conditions.

Effects of cocaine on the contents of neurohypophyseal hormones in the plasma and in different brain structures in rats.

The effects of acute and chronic cocaine treatments on the levels of the neurohypophyseal hormones oxytocin (OXT) and vasopressin (AVP) in the plasma and in different brain structures in rats were measured by radioimmunoassay (RIA). Acute cocaine treatment had no effect on the level of OXT in the plasma or in the amygdala, but increased OXT contents were measured in the hypothalamus and in the hippocampus. The OXT levels in the basal forebrain structures (including the septum and the nucleus accumbens) were decreased by a single dose of cocaine. The acute injection of cocaine increased the level of AVP in the plasma, and decreased contents of OXT were measured in the amygdala and in the basal forebrain. Repeated treatment with cocaine decreased the level of OXT in the plasma, hypothalamus and hippocampus. The AVP contents were decreased in all of the brain structures investigated, but no change was caused in the plasma level of AVP by repeated injections of cocaine. These results demonstrate complex, region-specific interactions between cocaine and the neurohypophyseal hormones in the brain and in the periphery underlying the alteration in behavioral and autonomic functions caused by acute and chronic cocaine exposure.

Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats.

Behavioural adaptation to and the effects of the neurohypophyseal peptide, oxytocin, on repeated treatment with cocaine were investigated in rats. The content of immunoreactive oxytocin in the plasma, hypothalamus and different limbic structures in the brain were also studied after treatment with cocaine, identical to that used in the behavioural experiment. Repeated administration of cocaine (7.5 mg/kg, s.c.) produced a behavioural tolerance to the stereotyped sniffing-inducing effect of the challenge doses (1.875, 3.75 and 7.5 mg/kg, s.c.) of cocaine on the fifth day, which was demonstrated by parallel shifting of the dose-response and time-effect curves of the test doses of cocaine. The development of tolerance was inhibited by pretreatment with oxytocin (0.05 micrograms, (s.c.), administered before each daily injection of cocaine. A smaller dose of oxytocin (0.005 micrograms, s.c.) had no effect in this model. A decreased amount of immunoreactive oxytocin was detected in the plasma, in the hypothalamus and in the hippocampus, after repeated treatment with cocaine. Replacement of oxytocin by local injection (100 pg) into the ventral hippocampus, before each daily administration of cocaine, prevented the development of tolerance to cocaine. These results suggest that endogenous oxytocin, localized in limbic-forebrain areas, may have an important regulatory role in the development of behavioural changes induced by the repeated administration of cocaine.

Two families with hereditary diabetes insipidus not due to osmoreceptor failure.

Two families with hereditary central diabetes insipidus (CDI) are reported. The pedigree in both families shows an autosomal dominant trait. The plasma arginine-8-vasopressin (AVP) determined by radioimmunoassay was markedly lower in these CDI patients than in healthy controls; the difference being even more pronounced after a hyperosmotic challenge. Since in the present study histamine also failed to increase the plasma AVP concentration, the authors consider it unlikely that an osmoreceptor failure would be implicated in the pathogenesis of CDI in these cases. The AVP concentration of the lumbar cerebrospinal fluid was also measured in two members of one of the families: the level found at the lower normal range indicates that some AVP secretion has been maintained in the extrahypothalamic vasopressinergic system of these patients.

Chromatographically identified oxytocin in the human peripheral nervous system.

Immunoreactive oxytocin (OXT) detected in extracts of human coeliac ganglia and nn. vagi was characterized by high-performance liquid chromatography (HPLC). HPLC/RIA examinations demonstrated that a major part of the immunoreactive material in both investigated areas co-eluted with a reference synthetic OXT, but in the extracts of coeliac ganglia a second immunoreactive peak was also observed.

Effect of vasopressin antagonist d(CH2)5Tyr(Et)VAVP on plasma arginine vasopressin level after osmotic stimulus.

The effect of the vasopressin antagonist d(CH2)5Tyr(Et)VAVP on the immunoreactive arginine vasopressin (AVP) level in plasma was studied in rats after osmotic stimulus. The blood samples were obtained from the eye plexus. An increased AVP level (193.2 +/- 70.0; control: 30.5 +/- 4.3 pmol/l) was detected after the administration of hypertonic NaCl solution. A much higher elevation of AVP level (1180.9 +/- 181.0 pmol/l) was observed when treatment with the antagonist was applied before the osmotic stimulus. The results indicate that this compound exerts a biological effect as a vasopressin receptor blocking agent through a mechanism of competitive antagonism.

Central effects of antiserum against human atrial natriuretic polypeptide on water and electrolyte metabolism and plasma arginine-8-vasopressin level in conscious rats.

Although synthetic atrial natriuretic polypeptide (ANP) is known to influence the water and electrolyte metabolism and arginine-8-vasopressin (AVP) secretion, the physiological role of endogenous ANP in the rat brain is still unclear. Accordingly, an investigation was made of the effects of intracerebroventricular (icv) administration of human h-ANP antiserum, which can neutralize endogenous ANP, on the water intake, urine output, urinary excretion of potassium and sodium, and plasma AVP level in normally hydrated rats. Apart from the water intake, all the parameters were also determined in 48-h water-deprived rats after h-ANP antiserum treatment. The icv administration of the h-ANP antiserum significantly increased the spontaneous water intake, urine output and urinary potassium excretion in rats given water ad libitum. These effects developed by 24 h after icv treatment. The h-ANP antiserum had no effect on the urine volume in 48-h water-deprived rats, suggesting a primary effect of endogenous ANP in the brain on the spontaneous water intake in rats given water ad libitum. These results suggest that ANP may have a physiologically important role in the central regulation of the water and electrolyte metabolism. The h-ANP antiserum did not alter the basal and dehydration-induced AVP release. This raises the possibility that the endogenous ANP in the brain may not participate in the control of AVP secretion.

Vasopressin(1-8) (des-glycinamide9-[Arg8]vasopressin) is an endogenous peptide present in rat plasma.

Using a radioimmunoassay for [Arg8]vasopressin(1-8) (des-glycinamide9-[Arg8]vasopressin; DGAVP) endogenous immunoreactive DGAVP (IR-DGAVP) was detected in extracts of plasma prepared from trunk blood of male Wistar rats. The IR-DGAVP was further characterized by reversed-phase high pressure liquid chromatography (HPLC). One of the two immunoreactive peaks obtained by HPLC coeluted with synthetic DGAVP and did not cross-react in a radioimmunoassay specific for [Arg8]vasopressin(1-9) (AVP). The other showed the chromatographical and radioimmunological characteristics of AVP. Analysis by HPLC of plasma prepared from fresh blood spiked with 3H-AVP indicated that under the experimental conditions employed no DGAVP was formed during extraction. The results indicate that DGAVP is present in rat plasma, possibly as an endogenous metabolite of AVP.

Characterization of oxytocin immunoreactivity in human sympathetic paravertebral ganglia.

Immunoreactive oxytocin (IR-OXT) detected in extracts of human lumbar sympathetic paravertebral ganglia was characterized by high-performance liquid chromatography (HPLC). The immunoreactive substance was found to elute at the same position as the reference preparation of oxytocin (OXT). The results revealed the presence of chromatographically identified OXT in human sympathetic ganglia.

[Regulation of vasopressin release in primary hypothyroidism and Addison's disease as well as in central diabetes insipidus]. / A vasopressin elválasztás szabályozásának vizsgálata primer hypothyreosisban és hypadreniában, valamint centrális diabetes insipidusban.

The osmoregulation of arginine-8-vasopressin (AVP) was investigated in 14 patients with primary hypothyroidism, in 6 with Addison's disease, and in 21 with central diabetes insipidus (CDI). In the latter disease the effect of histamine stimulus was also evaluated. Plasma AVP was measured by radioimmunoassay (RIA). Patients with primary hypothyroidism were classified into subgroups with elevated or normal basal levels of plasma AVP. A decreased osmotic threshold was found in hypothyroid patients with augmented basal AVP levels. Patients with Addison's disease exhibited an increased basal level of plasma AVP and a decreased osmotic threshold. CDI patients according to their AVP responses on osmotic stimulus fell into two groups: CDI I gave no response at all, while CDI II responded subnormally. CDI II exhibited blunted AVP release to histamine. The AVP reactions of the CDI I patients fell into two subgroups: CDI I/A had undetectable plasma AVP, whereas histamine evoked AVP release in CDI I/B. Patients with CDI II suffer from a partial CDI, while those with CDI I/A represent a complete form of the disease and CDI I/B presumably have an osmoreceptor failure.