Reduced lumbar CSF somatostatin levels in Alzheimer's disease

The lumbar CSF of control, demented (Alzheimer's and Korsakoff's) and schizophrenic patients was examined for markers of cholinergic, monoaminergic and peptidergic systems. In all groups, no alteration in CSF acetylcholinesterase was observed, with the monoamine metabolites homovanillic acid, monohydroxyphenylglycol, and 5-hydroxy-indole acetic acid expressing only minor alterations. In contrast, somatostatin (SRIH) was dramatically (50%) reduced in the CSF of Alzheimer's dementia (AD) and mixed dementia patients. These decreases in CSF SRIH correlate with previous reports of reductions in cortical SRIH in AD suggesting that such measurements may be useful markers of AD.     

Plasma arginine vasopressin concentrations and antidiuretic action of carbamazepine.

Twelve subjects given therapeutic doses of carbamazepine showed no change in their plasma electrolyte concentrations. Ten of the 12 had abnormal water metabolism, however, their ability to excrete water loads being decreased. Plasma arginine vasopressin (AVP) concentrations fell while the subjects were taking the drug, indicating that the mechanism is unlikely to be increased secretion of antidiuretic hormone. We suggest that the water-retaining property of carbamazepine is a physiological effect of the drug, mediated by increased renal sensitivity to normal plasma concentrations of AVP and resetting of osmoreceptors.     

Reduced nitric oxide metabolites in CSF of patients with tetrahydrobiopterin deficiency

We investigated CSF concentrations of nitrite and nitrate as indicators of nitric oxide (NO) production in patients with tetrahydrobiopterin (BH4) deficiencies. Patients with 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase and dihydropteridine reductase deficiencies exhibited decreased CSF nitrite + nitrate levels compared with healthy control subjects. Reduced levels of nitrite + nitrate were not influenced by oral administration of 2.5-5.0 mg/kg tetrahydrobiopterin. Our data indicate impaired NO synthase function in patients with BH4 deficiency and suggest possible involvement in the neuronal cell dysfunction.     

Effects of changes in plasma hepatic-portal and systemic osmolality on plasma concentrations of arginine vasopressin in conscious newborn calves

Systemic plasma concentrations of arginine vasopressin (AVP) were studied in three groups of 10-15 day-old conscious newborn calves. Animals in the first group (control group) and in the second group (systemic-hypertonic-injected group) received respectively isotonic and hypertonic (8 mmol NaCl/kg body weight) saline injection into the right jugular vein. Animals in the third group were fitted with chronic mesenteric and hepatic-portal catheters and received a 1 h-hypertonic saline infusion (2 mmol NaCl/kg body weight) into the main mesenteric vein. In animals in the second group there were parallel increases in systemic plasma concentration of Na+ (from 148.0 +/- 2.6 to 177 +/- 8 mmol/l; P less than 0.01), osmolality (from 289 +/- 2 to 319 +/- 4 mOsmol/kg H2O; P less than 0.01) and systemic plasma concentrations of AVP (from 4.2 +/- 0.4 to 11.1 +/- 0.6 pmol/l; P less than 0.01) 10 min after the injection. There were no significant changes in control animals. Hypertonic saline infusion into the main mesenteric vein in the third group induced an increase in concentration of Na+ (from 147.3 +/- 2.0 to 165.0 +/- 5.0 mmol/l; P less than 0.01) and osmolality (from 288 +/- 5 to 315 +/- 10 mOsmol/kg H2O; P less than 0.01) in hepatic-portal vein plasma but did not alter systemic plasma osmolality or concentrations of Na+ and AVP. This study demonstrates that the relationship between plasma concentrations of AVP and systemic osmolality is operative in the newborn calf but does not support the hypothesis that hepatic portal osmo-receptors sensitive to hyperosmolality influence AVP release.     

Radioimmunoassay of arginine vasopressin in human plasma.

Antibodies for the radioimmunoassay of arginine vasopressin (AVP) described here were produced in rabbits using synthetic AVP coupled to rabbit gamma-globulin with carbodiimide. In three out of six rabbits, significant antibody titres were obtained. Using the best antisera produced, 40% of labeled AVP was bound at a final dilution of 1:50.000. After iodination of synthetic AVP with 125I using the chloramin-T method, a gel filtration on Sephadex G-25 was performed to purify the iodinated AVP. For separation of antibody bound and free hormone, a second antibody precipitation was used. There was no crossreactivity with oxytocin. AVP was extracted from plasma after ammoniumsulfate precipitation of the proteins by adsorption to Florisil. The recovery of AVP added to plasma in amounts between 5-25 pg/ml was 60 +/- 15% (n equals 6). The minimum amount of AVP detectable was 1 pg per ml plasma. The plasma level in normal adults under standard conditions was 3.4 +/- 2.2 pg/ml. This is in agreement with data recently published by other researchers. The applicability and reproducibility was further tested in measurements of samples taken hourly during the entire day under water diuresis and after hormonal stimulation of AVP.     

Metabolism and synthesis of arginine vasopressin in conscious newborn sheep

Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate (MCR(AVP)). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate (PR(AVP)), and MCR(AVP) in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P < or = 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 +/- 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). MCR(AVP) was unchanged throughout the 1st mo (P > 0.2), averaging 205 +/- 17 ml.kg(-1).min(-1), and was associated with an elevated PR(AVP), 973 +/- 267 pg.kg(-1).min(-1), which also was unchanged (P > 0.1). After birth, MCR(AVP) and PR(AVP) are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st mo. The reason for the elevated PR(AVP) is unclear but may relate to increases in vascular volume associated with postnatal growth.     

CSF orexin-A/hypocretin-1 concentrations in patients with intracerebral hemorrhage (ICH)

Orexins/hypocretins are neuropeptides that have various physiological effects, including the regulation of both the feeding behavior neuroendocrine functions and sleep-wakefulness cycle. Recent studies have suggested that the orexin system may also be involved in neuronal damage in the clinical setting and animal experiments. The aim of this study was to examine the role of the hypothalamic orexin-A/hypocretin-1 system in patients with intracerebral hemorrhage (ICH). The CSF orexin-A/hypocretin-1 levels were measured in 11 ICH patients. CSF orexin-A/hypocretin-1 levels were low in ICH patients during the 13 days following the ICH event. The mean CSF orexin-A/hypocretin-1 levels were 61.1+/-22.3 (S.D.) pg/ml (range 27.5-106.9 pg/ml).The decreasing in the CSF orexin-A/hypocretin-1 levels was not related to the severity of ICH. The CSF orexin-A/hypocretin-1 levels were lower in the thalamic hemorrhage patients than those in other patients (48.5+/-23.3 pg/ml vs. 65.2+/-21.2 pg/ml; p=0.03.) These data indicate that orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in ICH patients.     

ACTH-releasing activity of urotensin I and ovine CRF: interactions with arginine vasotocin, isotocin and arginine vasopressin

The release of ACTH from superfused dispersed goldfish anterior pituitary cells was examined to determine if the neurohypophyseal peptides arginine vasotocin (AVT), isotocin (IST) or arginine vasopressin (AVP) potentiate the ACTH-releasing activities of the structurally homologous peptides urotensin I (UI) or ovine corticotropin-releasing factor (CRF). The ACTH-releasing activities of the neurohypophyseal peptides and UI or CRF were additive. AVT, IST or AVP failed to potentiate the ACTH-releasing activity of UI or CRF. These results suggest that in teleost fishes neurohypophyseal peptides have intrinsic ACTH-releasing activity but, unlike mammals, do not potentiate the release of ACTH evoked by CRF, or by the piscian CRF-like peptide, UI.     

The role of arginine vasopressin in alcohol dependence and withdrawal

The development and maintenance of tolerance to the physiological and behavioral effects of repeated exposure to ethanol can be altered markedly by the presence of arginine vasopressin (AVP). In addition, AVP has been implicated in the etiology of convulsions, including those induced by exposure to high ambient temperatures. In light of these findings, experiments were conducted to determine the role, if any, that AVP might play in the pathogenesis of alcohol-withdrawal convulsions. Thirty-two male Long Evans (LE) rats and 32 age-matched male homozygous Brattleboro (DI) rats (genetically deficient in AVP) were exposed to ethanol vapor concentrations adjusted to maintain blood alcohol levels of each rat at 150–350 mg/dl. Following at least 5 days of ethanol exposure, the animals were withdrawn. From 3–24 hr after cessation of ethanol administration, withdrawal severity was assessed by observing the response of each animal to a 60–120 sec period of auditory stimulation. No significant differences were observed in either latency to onset or severity of the convulsions in LE and DI rats upon ethanol withdrawal. Thus, alcohol-withdrawal convulsions, unlike hyperthermia-induced convulsions, may be mediated by a neurochemical substrate other than AVP.     

CSF hypocretin-1/orexin-A concentrations in patients with subarachnoid hemorrhage (SAH)

The aim of this study was to examine the role of the hypothalamic hypocretin/orexin system in complications of delayed ischemic neuronal deficit (DIND) resulting from symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). CSF hypocretin-1/orexin-A levels were measured in 15 SAH patients. DIND complications occurred in seven patients with symptomatic vasospasm. Hypocretin-1/orexin-A levels were low in SAH patients during the 10 days following the SAH event. CSF hypocretin-1/orexin-A levels were lower in patients with DIND complications than in those who did not develop DIND. A significant transient decline in CSF hypocretin-1/orexin-A levels was also observed at the onset of DIND in all patients with symptomatic vasospasm. The reduced hypocretin/orexin production observed in SAH patients may reflect reduced brain function due to the decrease in cerebral blood flow. These results, taken together with recent experimental findings in rats that indicate hypocretin receptor 1 (orexin 1 receptor) mRNA and protein are elevated following middle cerebral artery occlusion, suggest that a reduction in hypocretin/orexin production in SAH and DIND patients is associated with alterations in brain hypocretin/orexin signaling in response to ischemia.     

Radioimmunoassay of arginine vasopressin in the plasma and urine.

We introduced the radioimmunoassay (RIA) of arginine vasopressin (AVP) with standard AVP and antiserum to AVP (both Calibiochem). The sensitivity of the system was increased from the declared 4pg to 1 pg per tube by preparing AVP-125I of high specific activity (about 1,500 mCi/mg) and by modifying the reaction conditions. The sensitivity of the method was adequate for measuring AVP in urine and in concentrated plasma extracts, even under physiological conditions. Reliability of the results depended upon maintenance of approximately the same osmolarity in all the RIA samples. The mean plasma AVP level, uncorrected for AVP extraction losses, was 1.52 +/- 0.20 pg/ml for an ad libitum fluid intake; in fluid deprivation it rose in proportion to the osmolarity of the plasma to 5.83 +/- 0.42 pg/ml at 12 hours and to 19.09 +/- 4.51 pg/ml at 36 hours. Extraction recovery of added AVP was about 63%. The urinary AVP concentration varied according to the patients' state of hydratation from undetectable values at UOsm less than 200 mOsm/1 to a mean 16.5 +/- 7.9 pg/ml in the presence of an ad libitum fluid intake and to 29.1 +/- 7.5 pg/ml after 12 hours' and 117.2 +/- 13.7 pg/ml after 36 hours' deprivation of fluids.     

Isolation and structure elucidation of bovine pineal arginine vasopressin: arginine vasotocin not identified

A large number of reports have demonstrated the presence of neurohypophysial hormone-like peptides in mammalian pineal glands and an antigonadotropic function has been ascribed to pineal arginine vasotocin (AVT). We have undertaken large scale purification of bovine pineal neurohypophysial hormone-like substances which demonstrate mouse mammary milk-ejection activity (ME-activity) in vitro. Peptides with ME-activity were extracted from more than 5 kg of bovine pineal glands. ME-activity containing peptides were found in both high (Mr approximately 10,000-15,000) and low (Mr approximately 500-1000) Mr species from Sephadex G-25 chromatography of 0.2 N acetic acid extracts. After ultrafiltration in 5% formic acid, the neurohypophysial hormone-like peptides were localized to an ultrafiltration Mr 500-1000 retentate. A homogeneous peptide, which shared an identical retention time (RT) and amino acid sequence with synthetic 8-arginine vasopressin (AVP), was isolated by serial semipreparative high performance liquid chromatography. On the other hand, the non-mammalian nonapeptide AVT was not identified.     

Interaction of arginine vasopressin and corticotropin releasing factor demonstrated with an improved bioassay

We developed an improved in vivo bioassay for corticotropin releasing factor (CRF) by modifying the injection schedule in the standard chlorpromazine-morphine-pentobarbital assay procedure. A combined injection of chlorpromazine and morphine followed 75 min later by injection of pentobarbital produced low basal levels of corticosterone and rendered the animals highly sensitive to synthetic CRF but insensitive to the stress of ether or histamine. The lowest dose of CRF that significantly elevated plasma corticosterone levels was 0.01 micrograms/kg. Using this assay, we studied CRF-arginine vasopressin (AVP) interactions at doses that were expected to raise systemic peptide concentrations to levels measured in hypophysial portal blood. The threshold for a significant corticosterone response was found to be at least 250-fold lower for CRF-41 than for AVP. The order in which CRF and AVP are injected was also found to be important, potentiation being greater if CRF was given first. In addition, rats deprived of water for 24 hr were more sensitive to CRF than normally hydrated animals.