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Arginine vasopressin (AVP) stimulates adrenocorticotropin (ACTH) secretion from corticotroph cells of the anterior pituitary via activation of the V1b vasopressin receptor, a member of the G protein-coupled receptor (GPCR) family. Recently, we have shown that treatment of ovine anterior pituitary cells with AVP for short periods results in reduced responsiveness to subsequent stimulation with AVP. The aim of this study was to investigate mechanisms involved in this desensitization process. Among the GPCR family, rapid desensitization is commonly mediated by receptor phosphorylation, with resensitization being mediated by internalization and subsequent dephosphorylation of the receptors by protein phosphatases. Since desensitization of V1a vasopressin receptors is mediated by protein kinase C-mediated receptor phosphorylation, we investigated the involvement of this enzyme in desensitization of the ACTH response to AVP. Treatment of perifused ovine anterior pituitary cells with the specific protein kinase C (PKC) activator 1,2-dioctanoyl-sn-glycerol (300 μM) did not induce any reduction in response to a subsequent 5-min stimulation with 100 nM AVP, despite potently stimulating ACTH secretion. Likewise, the results obtained using the PKC inhibitor Ro 31-8220 were not consistent with involvement of PKC in AVP desensitization: 2 μM Ro 31-8220 did not reduce the ability of a 10 nM AVP pretreatment to induce desensitization to a subsequent stimulation with 100 nM AVP. Pharmacologic blockade of receptor internalization by treatment with 0.25 mg/ml concanavalin A significantly impaired the ability of a 15-min pretreatment with 10 nM AVP to induce desensitization, rather than affecting resensitization. Treatment with 10 nM okadaic acid, an inhibitor of protein phosphatase 1 and 2A, had no effect on either resensitization or desensitization. In contrast, inhibition of protein phosphatase 2B (PP2B) with 1 μM FK506 decreased the rate of resensitization: complete recovery from desensitization took 40 min, whereas in controls recovery was complete 20 min after termination of the pretreatment. These results indicate that desensitization of the ACTH response to AVP is not mediated by PKC-catalyzed phosphorylation, suggesting subtype-specific differences in the regulation of V1a and V1b vasopressin receptors. The data demonstrate that desensitization was dependent, at least in part, upon receptor internalization and that resensitization was dependent upon PP2B-mediated receptor dephosphorylation.
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Following repeated or prolonged exposure to either corticotrophin-releasing hormone (CRH) or arginine vasopressin (AVP), pituitary adrenocorticotrophin (ACTH) responsiveness is reduced. This study compared the characteristics of desensitization to CRH and AVP in perifused ovine anterior pituitary cells. Desensitization to AVP occurred at relatively low AVP concentrations and was both rapid and readily reversible. Treatment for 25 min with AVP at concentrations greater than 2 nM caused significant reductions in the response to a subsequent 5 min 100 nM AVP pulse (IC(50)=6.54 nM). Significant desensitization was observed following pretreatment with 5 nM AVP for as briefly as 5 min. Desensitization was greater following a 10 min pretreatment, but longer exposures caused no further increase. Resensitization was complete within 40 min following 15 min treatment with 10 nM AVP. Continuous perifusion with 0.01 nM CRH had no effect on AVP-induced desensitization. Treatment with 0.1 nM CRH for either 25 or 50 min caused no reduction in the response to a subsequent 5 min stimulation with 10 nM CRH. When the pretreatment concentration was increased to 1 nM significant desensitization was observed, with a greater reduction in response occurring after 50 min treatment. Recovery of responsiveness was progressive following 50 min treatment with 1 nM CRH and was complete after 100 min. Our data show that in the sheep AVP desensitization can occur at concentrations and durations of AVP exposure within the endogenous ranges. This suggests that desensitization may play a key role in regulating ACTH secretion in vivo. If, as has been suggested, CRH acts to set corticotroph gain while AVP is the main dynamic regulator, any change in responsiveness to CRH may significantly influence the overall control of ACTH secretion.
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SUMMARY
The concentrations of oestrone and oestradiol in jugular vein plasma during the bovine oestrous cycle were measured using a fluorescence assay. The highest levels of both oestrogens were found on the 19th and 20th days of a standardized 21-day cycle, with the peak of oestrone occurring slightly before that of oestradiol. Oestrone values ranged from 23·1 to 226·9 ng/100ml and oestradiol varied between 17·6 and 117·5 ng/100 ml. Relatively high values for oestrone concentrations were found on days 6, 7 and 8. These values are comparable to those observed in the ovarian vein blood of the ewe, using both the present method and radioimmunoassay.
The relationship between the oestrogen concentrations reported here and the levels of other hormones during the bovine oestrous cycle is discussed.
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ABSTRACT
The involvement of endogenous opioid peptides in the stress response was investigated by measuring plasma concentrations of Met-enkephalin-like immunoreactivity (MLI), adrenaline and noradrenaline during insulin-induced hypoglycaemia in conscious greyhounds. Moreover, the molecular forms of circulating MLI were characterized using gel filtration chromatography.
In the first group of animals, i.v. administration of insulin (0·3 units/kg) provoked marked hypoglycaemia (blood glucose concentrations fell from 4·4 ± 0·1 to 1·5 ±0·2 mmol/l; mean ± s.e.m.) which was associated with significant (P< 0·001) rises in plasma MLI concentrations from a basal concentration of 45 ± 8 to a peak of 189 ±39 ng/l.
A within-subject study comparing five different insulin doses ranging from 0·004 to 0·3 units/kg showed dose-related effects on blood glucose with nadir concentrations of 4·1 ± 0·6 mmol/l (after the smallest dose of insulin) and 0·8 ± 0·1 mmol/l (after the largest dose of insulin). This was associated with dose-related rises in plasma MLI with peak concentrations of 56±17 and 558 ± 35 ng/l, plasma adrenaline with peak concentrations of 0·45± 0·06 and 15·76±1·33 nmol/l and plasma noradrenaline with peak concentrations of 0·49 ± 0·07 and 2·27 ± 0·45 nmol/l following the smallest and largest doses of insulin respectively. These results are the first demonstration of raised plasma MLI concentrations following hypoglycaemia. Moreover, they show that the hormonal responses vary with the degree of hypoglycaemia achieved. Together with reports by other investigators these findings might suggest opioid modulation of the responses of the sympathoadrenal system to hypoglycaemia. These responses were, however, not modified by the opioid antagonist naloxone.
Gel filtration chromatography of neat (unextracted) plasma revealed the predominance of large molecular weight enkephalin-containing peptides, with approximate molecular weights of 18 000 and 8000, both basally and following stimulation by hypoglycaemia.
J. Endocr. (1987) 114,81–87
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Abstract
Although GnRH is believed to be the primary secretagogue for LH, oxytocin has also been shown to stimulate LH release from the anterior pituitary. We investigated the possibility that the two secretagogues interact in the modulation of LH release. Anterior pituitaries were removed from adult female rats at pro-oestrus, and tissue pieces were pre-incubated in oxytocin for 3 h prior to being stimulated with 15 min pulses of GnRH. LH output over the 1 h period from the beginning of the GnRH pulse was determined. Control incubations were carried out in the absence of oxytocin, and background secretory activities without GnRH stimulation were also determined.
Tissue which was pre-exposed to oxytocin (0·012–1·25 μm) had an increased LH response to GnRH (1·25 nm). The increase was larger than the sum of the LH outputs obtained with oxytocin and GnRH separately, revealing that oxytocin synergistically enhanced LH secretion elicited by GnRH (P<0·05; ANOVA). If stimulation by GnRH was delayed for 2 h after incubation with oxytocin, an increase in LH secretion was still observed, indicating that oxytocin-induced modulation did not rapidly disappear. Oxytocin pre-incubation was observed to result in an increase of maximal GnRH-induced LH output (P<0·001; t-test), as well as an increase of intermediate responses.
The LH response of the anterior pituitary to subsequent pulses of GnRH was modified by the self-priming process. The effect of oxytocin pretreatment on the response of primed tissue to GnRH was also investigated. It was found that pre-incubation in oxytocin also enhanced the LH response of primed tissue to GnRH.
The study has revealed that oxytocin increases the LH output of anterior pituitary tissue in response to GnRH. The effect occurs on both GnRH-primed and unprimed tissues. The results suggest that oxytocin has the potential to regulate the dynamics of the pro-oestrous LH surge.
Journal of Endocrinology (1995) 145, 113–119
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ABSTRACT
The mechanisms involved in the release of Metenkephalin-like immunoreactivity (MLI) into the circulation following oral administration of ethanol and chlorpropamide were investigated in dogs. The origin of plasma MLI and the sites where it may be metabolized were also studied. Moreover, the molecular nature of circulating MLI was characterized.
In conscious animals oral administration of ethanol (0·15 ml/kg) led to a significant (P<0·01) rise in plasma MLI concentrations in chlorpropamidepretreated animals from a basal level of 43 ± 6 (mean ± s.e.m.) to a peak of 66 ± 8 ng/l. Similar rises in MLI concentrations were observed following administration of ethanol with disulfiram and ethanol with chlorpropamide and captopril. In contrast, the administration of ethanol alone or ethanol with 4-methylpyrazole resulted in a decrease in plasma MLI concentrations.
Comparisons of two different doses of i.v. acetaldehyde, the first metabolite of ethanol, showed that plasma MLI concentrations rose significantly (P<0·05) only after the larger dose (8 mg/kg), rising from 45±7 to 81 ± 18 ng/l. These results suggest that acetaldehyde is the active component in the chlorpropamide+ ethanol-induced MLI secretion.
Plasma MLI was also measured following acetaldehyde infusion in adrenalectomized dogs with and without hexamethonium treatment. Acute bilateral adrenalectomy resulted in a decrease (P<0·05) in plasma MLI concentrations, but the levels remained detectable. Moreover, subsequent acetaldehyde infusion led to rises in plasma MLI similar to those observed in animals with intact adrenals. These MLI responses were not altered by the concurrent i.v. administration of hexamethonium. Gel filtration chromatography revealed that Met-enkephalin exists in the circulation predominantly in larger molecular forms with approximate sizes of 18 000 and 8000 Da in the basal state, after stimulation and following adrenalectomy.
Journal of Endocrinology (1989) 120, 473–480
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* Zoology Department, University of St Andrews, Scotland, KY16 9TS, and † Medical Research Council Blood Pressure Research Unit, Western Infirmary, Glasgow, G11 6NT
(Received 2 April 1976)
Although several corticosteroids have been reported to be present in teleost plasma (review by Idler, 1972) relatively few studies have taken adequate steps to ensure that these compounds have been reliably characterized. Methods of establishing the identity of steroids have been discussed by Brooks, Brooks, Fotherby, Grant, Klopper & Klyne (1970) and those related to teleost studies have been reviewed and assessed by Idler (1972). This report describes the analysis of a small number of plasma samples from Salmonidae caught in Loch Lomond, Scotland. Analysis was by a highly specific method based on gas–liquid chromatography (g.l.c.) which satisfies many of the criteria suggested by the above authors.
Specimens of four salmonid species were collected by means of seine or gill-nets. Coregonus lavaretus,
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SUMMARY
Cortisol utilization by salivary glands, kidneys and adrenals of various mammals has been compared by using a standard histochemical technique for the demonstration of hydroxysteroid dehydrogenases. 11β-Hydroxysteroid dehydrogenase activity was localized in salivary gland ducts, renal collecting and convoluted tubules and in the adrenal cortex of some species. There was no obvious relationship between the levels of enzyme activity in the salivary glands, kidneys and adrenals. Neither was the presence of 11β-hydroxysteroid dehydrogenase in salivary glands particularly associated with mucous or serous secretion, nor were sex differences in levels of activity evident.
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Abstract
Human melanocytes, maintained on bovine corneal endothelium-derived extracellular matrix for at least 4 days in the absence of phorbol 12-myristate 13-acetate (PMA) and cholera toxin (CT), displayed increased tyrosinase activity when exposed to several pro-opiomelanocortinderived (POMC) peptides. Melanocytes from 9 of 14 donors showed significantly increased tyrosinase activity after treatment with adrenocorticotropic hormone (ACTH; mean increase 320±107 (s.e.m.)% of control, P<0·005), while melanocytes from 8 of 13 donors increased tyrosinase in the presence of diacetyl-melanocyte stimulating hormone (di-MSH; mean increase 223±31 (s.e.m.)% of control, P<0·005). Maximal increases in tyrosinase were seen after treatment with 10−10 m ACTH and with 10−6 m di-MSH. In two cell cultures which showed tyrosinase stimulation, melanin synthesis was similarly increased in the presence of added POMC peptides. PMA but not CT increased tyrosinase activity in melanocytes cultured under these conditions. In the presence of staurosporine, an inhibitor of protein kinase C (PKC), the magnitude of the increase in tyrosinase due to PMA, ACTH and di-MSH was significantly reduced. These results indicate that tyrosinase activity in melanocytes from most human donors, under appropriate conditions, is susceptible to the stimulatory effects of POMC peptides, that ACTH is considerably more potent than di-MSH in this test system and that in human cells the PKC pathway may be important in modulating melanogenesis.
Journal of Endocrinology (1995) 146, 439–447
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SUMMARY
The excretion of iodine in urine, saliva, gastric juice and sweat has been studied by using 131I-labelled monoiodotyrosine in a patient with the dehalogenase type of dyshormonogenesis. Iodinated components 'x', iodide, monoiodotyrosine and 'y' were found in the urine. A previously undescribed component (compound 'u') accounted for a large fraction of the urinary radioactive iodine. Organic iodinated compounds were not excreted in the saliva. Only inorganic iodide was found in the gastric juice. No organic iodine was detected in the sweat. The plasma inorganic iodine (PII) derived from salivary iodine measurements gave low values indicative of iodine deficiency. The PII values obtained from the urinary iodine were falsely high due to the presence of organic iodinated compounds.
