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W W Vale

Publications and source records attributed to W W Vale.

At least 181 records · Page 10Linked to original sources
PubMed1984

Corticotropin-releasing factor receptors in rat pituitary gland: autoradiographic localization.

Corticotropin-releasing factor (CRF) receptors were localized in rat pituitary gland by an in vitro labeling light microscopic autoradiographic technique using the radioiodinate ovine CRF analog, [Nle21,125I-Tyr32]-CRF. Our data confirms the existence of CRF receptors in anterior pituitary and demonstrates the presence of specific CRF binding sites in the intermediate lobe of rat pituitary. The distribution of CRF binding sites closely resembles the clustering of corticotrophs in anterior lobe and the uniform distribution of opiomelanocortin-producing cells in the intermediate pituitary. These results suggest that endogenous CRF plays a physiological role in regulating secretion of pro-opiomelanocortin-derived peptides from both anterior and intermediate lobes of rat pituitary.

Animals↗
PubMed1984

Calcitonin gene-related peptide acts within the central nervous system to inhibit gastric acid secretion.

The central nervous system effect of calcitonin gene-related peptide (CGRP) on gastric acid secretion was studied in conscious freely moving rats. CGRP (220 fmol to 2.2 nmol) injected into the lateral cerebral ventricle or intravenously inhibited gastric acid secretion. Intravenous passive immunization with CGRP antiserum prevented the inhibitory effect of CGRP following intravenous but not intracerebroventricular administration. Adrenalectomy and noradrenergic blockade with bretylium tosylate did not significantly alter the inhibitory action of CGRP given intracerebroventricularly on gastric secretion. These studies indicate that CGRP acts within the central nervous system to potently decrease gastric acid secretion by mechanism(s) not dependent on intact sympathetic nervous function.

Adrenalectomy↗
PubMed1984

Somatostatin desensitization in rat anterior pituitary cells.

The possibility that desensitization to the inhibitory effects of somatostatin (SS) might develop following chronic exposure to this tetradecapeptide was examined in cultured rat anterior pituitary cells. Pretreatment with 1 microM SS for 48 h caused a shift in the IC50 of SS to inhibit 3-isobutyl-1-methylxanthine (IBMX) or growth hormone-releasing factor (GRF)-induced growth hormone (GH) and TRH + IBMX-induced thyroid-stimulating hormone (TSH) release by more than 2 orders of magnitude. Refractoriness developed after 12 h of exposure to doses of SS of 10 nM or more and became maximal at 48 h. Restoration of SS responsiveness followed a similar time-course upon removal of the peptide. In superfused cells, 10 nM SS lowered GH secretion rates to less than 5 ng/min within 2 h, but GH release began to rise after 16 h despite the continued presence of SS. However, when somatostatin was delivered in pulses, it remained fully effective for more than 36 h. Somatostatin-28 was also capable of inducing refractoriness in cultured pituitary cells. However, cells made refractory to either SS-14 or SS-28 were not made refractory to the same extent to the other form of somatostatin. These results indicate that the pituitary can become desensitized to the inhibitory actions of somatostatin just as it does to the stimulatory actions of the other hypothalamic releasing hormones.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Co-expression of corticotropin-releasing factor and vasopressin immunoreactivity in parvocellular neurosecretory neurons of the adrenalectomized rat.

To clarify the anatomical organization that allows for the synergy of vasopressin and oxytocin with corticotropin-releasing factor (CRF) in promoting adrenocorticotropic hormone secretion from the anterior pituitary, immunohistochemical double staining methods were used to compare the distribution of these peptides in the hypothalamic paraventricular nucleus of normal, colchicine-treated, and adrenalectomized male rats. In untreated animals, a few CRF-stained cells were found in the parvocellular division of the paraventricular nucleus, while brightly stained oxytocin- and vasopressin-immunoreactive cells were centered in the magnocellular division. In animals treated with colchicine, and inhibitor of axonal transport, large numbers of CRF-stained cells were found in the parvocellular division of the nucleus, and 1-2% of these also stained with antivasopressin. As reported previously, a substantial number of oxytocin-stained cells, centered in a discrete anterior part of the magnocellular division, also expressed CRF immunoreactivity. In contrast, after adrenalectomy, CRF immunostaining of cells in the parvocellular division was enhanced selectively and greater than 70% of these cells also stained positively for vasopressin. The distribution of oxytocin-stained cells was not influenced by adrenalectomy. The unusual localization of vasopressin immunoreactivity in parvocellular neurosecretory neurons in the adrenalectomized rat suggests that a single population of cells can produce CRF and vasopressin, both of which are potent promoters of adrenocorticotropic hormone secretion. These findings indicate that there is a state-dependent plasticity in the expression of biologically active peptides by individual neuroendocrine neurons.

Adrenalectomy↗
PubMed1984

Picrotoxinin and phorbol-12-myristate-13-acetate stimulate the secretion of multiple forms of somatostatin from cultured rat brain cells.

The molecular forms of somatostatin (SRIF) secreted by cultured fetal rat brain cells were resolved using reverse phase high performance liquid chromatography followed by radioimmunoassay. Multiple forms of SRIF-like immunoactivity were detected in media from cells treated with either picrotoxinin, phorbol-12-myristate-13-acetate, or high potassium. For stimulated cells, elevated levels of an SRIF-28-like molecule, an SRIF-14-like molecule, and a hydrophobic SRIF-like molecule were observed compared to basal conditions. All three forms of SRIF-like molecules were also detected in acid extracts of whole cells. The data are consistent with the possibility that secretion of multiple SRIFs , including SRIF-28, may be regulated by multiple effectors and mechanisms.

Animals↗
PubMed1984

Differential suppression of FSH and LH secretion by follicular fluid in the presence or absence of GnRH.

The differential role of porcine follicular fluid (pFF) in regulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release in vivo in situations of different gonadotropin releasing hormone (GnRH) backgrounds was studied. In experiment 1, 2-week ovariectomized rats injected intravenously with 4, 16 or 64 mg of protein from pFF, showed a dose-dependent suppression of FSH over time, with a maximal suppression to 40% of control values by 10 h. LH levels were slightly, but significantly, elevated by the two lower doses, but not by the highest dose of pFF. In experiment 2, 64 mg pFF was superimposed (i.v. injection) in ovariectomized rats injected subcutaneously with a high dose of GnRH antagonist (500 micrograms) 24 h earlier. The pFF suppressed FSH 35% below the level achieved in the absence of GnRH stimulation, with no effect on LH. In experiment 3, the rise in FSH secretion in acutely ovariectomized rats was shown to be inhibited by 8 or 32 mg pFF administered intravenously 3.5 h after surgery. Injection of GnRH (250 or 1,000 ng) 4.5 h after pFF could not overcome the inhibitory action of pFF on FSH, although non-pFF-treated controls responded in a dose-dependent fashion to GnRH stimulation. The expected LH response to GnRH was not affected by pFF, except in the group receiving 1,000 ng GnRH and 8 mg pFF. In these rats, LH was enhanced in one trial, but suppressed in a replicate trial, illustrating the inconsistent effects of pFF on LH under conditions of high GnRH stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Corticotropin-releasing factor regulates proopiomelanocortin messenger ribonucleic acid levels in vivo.

Ovine corticotropin-releasing factor (oCRF) was administered to male rats for 3-15 days. Continuous intravenous infusion, repeated subcutaneous, and intracerebroventricular injections of oCRF resulted in a 50-100% increase in messenger ribonucleic acid (mRNA) coding for proopiomelanocortin (POMC) in the anterior pituitaries (AP) of these animals. The synthetic glucocorticoid, dexamethasone, reversed the actions of oCRF. None of the above treatments altered POMC mRNA content in the neurointermediate lobe. Bilateral adrenalectomy enhanced POMC mRNA levels 4.8-fold. To determine whether this effect was dependent on increased hypothalamic production and release of CRF, a bilateral ablation of the paraventricular nucleus (PVN), known to contain CRF neurons directly involved in ACTH secretion, was performed. 6 days after the PVN destruction a parallel 75% reduction of both stalk-median eminence CRF-like immunoreactivity and plasma ACTH had occurred. The AP content of POMC mRNA decreased by 53%, while the ACTH content increased by 56%. These observations suggest that CRF regulates the biosynthesis of POMC-derived polypeptide products in the AP, while the peptide does not seem to be directly involved in intermediate lobe POMC biosynthesis. The reduction of POMC mRNA levels following PVN destruction demonstrates that CRF and other substances located in the nucleus may cause the increased POMC gene transcription following adrenalectomy.

Adrenalectomy↗
PubMed1984

Somatostatin analogs inhibit somatostatin secretion from cultured hypothalamus cells.

The effect of somatostatin (SRIF) analogs on the secretion of radioimmunoassayable SRIF (SRIF-LI) was studied in the model system of fetal rat hypothalamus cells maintained in long-term, primary dispersed culture. These experiments exploited the biologic activity of certain synthetic SRIFs which cross-react poorly in our standard RIA for SRIF. Carbachol-stimulated SRIF-LI secretion was suppressed by [DTrp8]-SRIF-14, [DTrp22]-SRIF-28 and the octapeptide, des-AA1,2,4,5,12,13[DTrp8]-SRIF. Effective concentrations of synthetic analogs were at or below 1 nM. des-Trp8-SRIF-14, an analog inactive in all other SRIF biological assays, was similarly ineffective in this assay system at doses up to 10 nM. Following removal of peptide by washing, peptide-treated and control cells responded similarly to depolarization with high potassium buffer. The data demonstrate a direct action of SRIF analogs on the hypothalamus to suppress SRIF-LI release and are consistent with the possibility that an endogenous peptide participates in 'ultrashortloop' negative feedback control of its own secretion in the intact animal.

Animals↗
PubMed1984

Effect of paraventricular lesions on corticotropin-releasing factor (CRF)-like immunoreactivity in the stalk-median eminence: studies on the adrenocorticotropin response to ether stress and exogenous CRF.

Corticotropin-releasing factor-like immunoreactivity (CRF) and plasma ACTH were measured in rats bearing bilateral lesions of the paraventricular nucleus (PVN). Four to 6 days after stereotaxic surgery, CRF-like immunoreactivity content of the stalk-median eminence was reduced by 87-90% and the ACTH response to a 3-min ether stress was greatly attenuated (70-85% reduction). In order to differentiate between possible effects of CRF, catecholamines, and arginine vasopressin (AVP), the following treatments were used: group I, sham/vehicle; group II, sham/AVP-antagonist; group III, sham/ganglionic blocker chorisondamine; group IV, PVN-lesions/vehicle; group V, PVN-lesion/AVP antagonist; group VI, PVN-lesion/chlorisondamine. Blood was sampled at 0, 5, and 15 min after a 3-min exposure to ether vapor. PVN lesions alone greatly attenuated the ACTH response to ether stress by 70-85% (group IV), whereas basal ACTH levels were not affected. Chlorisondamine alone (group III) was as effective as PVN lesions in reducing the secretion of ACTH due to stress. When PVN-lesioned animals were treated with the ganglionic blocker, the residual ACTH response was completely abolished (group VI). The AVP-antagonist alone reduced the response at +15 min by 45%, whereas the antagonist given to PVN-lesioned animals completely abolished the response at 15 min. Injection of 0.15 nmol ovine CRF into PVN-lesioned rats resulted in a dramatically increased ACTH response (328% at 15 min) in comparison to the response of sham-operated rats. We conclude that: 1) CRF originating from neurons within the PVN is the predominant regulator of stress-induced ACTH secretion; 2) catecholamines and AVP are involved in mediating stress-induced ACTH secretion, most probably as CRF-potentiating agents; and 3) pituitary hyperresponsiveness to exogenous CRF results from removal of endogenous CRF.

Adrenocorticotropic Hormone↗
PubMed1984

Chronic exposure of cultured rat anterior pituitary cells to GRF causes partial loss of responsiveness to GRF.

Pretreatment of primary cultures of rat anterior pituitary cells with 500 pM rhGRF for 24 h resulted in a partial loss of responsiveness to GRF. When pretreated cells were rechallenged with increasing concentrations of rhGRF, maximal GH secretion was significantly lower than control, since prolonged exposure to the peptide resulted in depletion of releasable GH pools: 3.04 +/- 0.39 and 0.63 +/- 0.08 micrograms GH per 0.15 X 10(6) cells in control and treated cells, respectively. Possible desensitization, however, was indicated, since chronic exposure to rhGRF increased the EC50 for GH secretion by 5.5-fold. Pretreatment with 2 mM 8BrcAMP for 24 h also caused significant depletion of cellular GH. Consequently, maximal GH secretory response of these cells was blunted as well. However, in contrast to rhGRF-pretreatment, 8BrcAMP-pretreatment did not significantly affect the EC50 value for GH secretion. As another index for cellular responsiveness, cAMP production was also monitored. After a 24-h incubation with 500 pM rhGRF, attenuation of adenylate cyclase activity was evident, since the EC50 value for cAMP production was 2.8-fold greater than control. These results suggest that prolonged pretreatment with GRF results in a partial loss of responsiveness to GRF and this may be explained by desensitization and to some extent by depletion of GH stores.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1984

Growth hormone release in response to human pancreatic tumor growth hormone-releasing hormone-40 in children with short stature.

Forty children with short stature were evaluated for GH reserve after pharmacological tests and after a single iv injection of human pancreatic tumor GH-releasing hormone [hpGRH-40). These children were grouped into four diagnostic categories: 1) idiopathic GH deficiency (n = 10); 2) organic hypopituitarism (n = 7); 3) intrauterine growth retardation (n = 5); and 4) constitutional delay of growth and/or familial short stature (n = 18), by standard clinical criteria and physiological and pharmacological tests of GH reserve. Venous blood was sampled for GH concentrations on 2 consecutive days: on day 1, after the iv administration of L-arginine (0.5 g/kg for 30 min) and oral administration of L-dopa (9 mg/kg), and on day 2, after the administration of hpGRH-40, 3.3 micrograms/kg, as an iv bolus. No GH-deficient patient in categories 1 or 2 increased his/her circulating GH concentration to more than 7 ng/ml after the arginine-L-dopa test; however, six children had marked GH responses after hpGRH-40 administration. As a group the lowest peak responses (mean +/- SE) to GRH were found in the organic hypopituitary (3.4 +/- 1.1 ng/ml) and in the idiopathic GH deficiency (8.2 +/- 2.4 ng/ml) categories. All children in the intrauterine growth retardation and constitutional delay of growth (controls for the GH-deficient children) responded briskly to hpGRH-40, although there was wide variation of the peak GH levels (5-51 ng/ml). Circulating concentrations of somatomedin-C did not differ in subjects in any category 24 h after hpGRH-40 injection when compared to basal values. These data indicate that hpGRH-40 can be employed to evaluate GH reseve in short children and may be useful in the diagnosis of hypothalamic-pituitary disorders.

Adolescent↗
PubMed1984

Corticotropin-releasing factor: co-expression within distinct subsets of oxytocin-, vasopressin-, and neurotensin-immunoreactive neurons in the hypothalamus of the male rat.

Two immunohistochemical methods that allow the concurrent localization of neuroactive substances within individual neurons have been used to identify, count, and chart the distribution of corticotropin-releasing factor (CRF)-immunoreactive cells in the paraventricular nucleus of the hypothalamus (PVH) that may also contain an additional peptide. In colchicine-treated male rats a moderate number of oxytocin-stained cells, localized primarily in a discrete, anterior part of the magnocellular division of the nucleus, was found also to stain positively for CRF. Similarly, oxytocin and CRF immunoreactivity were jointly expressed in magnocellular neurons distributed diffusely in the supraoptic nucleus. Smaller numbers of vasopressin- and neurotensin-stained neurons centered in specific parts of the parvocellular division of the PVH were stained with antisera against CRF. Possible mechanisms whereby the function of subsets of magnocellular and parvocellular neurosecretory neurons can be modulated differentially are discussed.

Animals↗
PubMed1983

Biological effects of cysteamine: relationship to somatostatin depletion.

Cysteamine given subcutaneously to rats decreases brain concentrations of somatostatin-like immunoactivity (SLI) but does not affect vasopressin-like immunoactivity as determined by radioimmunoassay and immunocytochemistry. Since somatostatin-related peptides act within the central nervous system (CNS) to increase body temperature and decrease adrenal epinephrine secretion, changes in these parameters were assessed following cysteamine administration. Cysteamine administration lowers oxygen consumption and body temperature, and elevates plasma concentrations of epinephrine, glucose, insulin and glucagon. The lowering of body temperature and elevation of plasma epinephrine is prevented by CNS administration of the CNS-selective somatostatin analog desAA1,2,4,5,12,13[D-Trp8 ))somatostatin. The CNS actions of somatostatin-related peptides are opposite to the effects of cysteamine. The observations are consistent with the possibility that brain somatostatin-related peptides are involved in regulation of body temperature and adrenal epinephrine secretion.

Animals↗
PubMed1983

Desensitization of cultured pituitary cells to gonadotropin-releasing hormone: evidence for a post-receptor mechanism.

Previous reports have demonstrated that chronic exposure to high concentrations of gonadotropin-releasing hormone (GnRH) induces a state of refractoriness to GnRH in the pituitary. In order to determine the role of the GnRH receptor in desensitization, we have compared the ability of GnRH to stimulate luteinizing hormone (LH) secretion with changes in GnRH binding. Cultured rat anterior pituitary cells exposed to 1 nM GnRH for 12 h became refractory to this dose of GnRH but were able to release LH in response to higher concentration of GnRH. Exposure to 1 nM or 10 nM GnRH not only caused a shift in the EC50 of GnRH to release LH from 0.28 nM to about 4.5 nM, but also produced a decrease in the maximal response which could not be fully explained by the reduced LH cell content. Examination of GnRH receptor binding to cells pretreated with similar doses of GnRH revealed no change in receptor affinity and a 10-90% increase in receptor number. This paradoxical up-regulation of GnRH receptor number occurred over a period of 6 h and was completely abolished in the presence of cycloheximide. The continuous presence of GnRH was not required for receptor up-regulation since pulses of GnRH were just as effective in increasing GnRH binding. The results indicate that changes in GnRH receptor affinity and number do not always parallel the changes in pituitary responsiveness to GnRH. Therefore, GnRH-induced desensitization cannot be fully explained by down-regulation of receptors and must involve a post-receptor mechanisms.

Animals↗
PubMed1983

Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study.

The distribution of corticotropin-releasing factor (CRF)-immunoreactive cells and fibers has been examined in the brains of normal adult rats, and in the brains of animals that had been pretreated with intraventricular injections of colchicine, or had been adrenalectomized 3-60 days before perfusion. The results suggest that CRF immunoreactivity is localized in at least three functionally distinct systems. First, most of the CRF-stained fibers in the neurohemal zone of the median eminence, which presumably modulate the release of ACTH and beta-endorphin from the pituitary, appear to arise in the paraventricular nucleus of the hypothalamus (PVH). About 2,000 CRF-stained cells are distributed throughout all eight parts of the PVH, although a majority (80%) of the cells are concentrated in the parvocellular division, and a smaller number (about 15%) are found in parts of the magnocellular division in which oxytocinergic cells predominate. This appears to be the only CRF-stained pathway in the brain that is affected (increased staining intensity) by adrenalectomy. Second, a series of cell groups in the basal telencephalon, hypothalamus, and brain stem that are known to play a role in the mediation of autonomic responses contain CRF-stained neurons. These areas, which are interconnected by stained fibers in the medial forebrain bundle and the periventricular system, include the central nucleus of the amygdala, substantia innominata, bed nucleus of the stria terminalis, medial and lateral preoptic areas, lateral hypothalamic area, central gray, laterodorsal tegmental nucleus, locus ceruleus, parabrachial nucleus, dorsal vagal complex, and regions containing the A1 and A5 catecholamine cell groups. And third, scattered CRF-stained cells are found throughout most areas of the cerebral cortex. Most such cells are confined to layers II and III in the neocortex, and their bipolar shape suggests that they are interneurons. These cells are most common in limbic regions including prefrontal areas, the cingulate gyrus, and areas bordering the rhinal fissure. Scattered immunoreactive cells are also found in dorsal parts of the dentate gyrus and Ammon's horn. These results suggest that the PVH plays a critical role in the modulation of ACTH and beta-endorphin release from the pituitary, and that CRF-containing pathways in the brain are involved in the mediation of autonomic responses.

Adrenalectomy↗
PubMed1983

Muscarinic cholinergic stimulation of somatostatin secretion from long term dispersed cell cultures of fetal rat hypothalamus: inhibition by gamma-aminobutyric acid and serotonin.

Regulation of somatostatin (SS) secretion was studied in an in vitro system using collagenase-dispersed cells from fetal rat hypothalamus maintained in long term monolayer culture. Cultured cells exhibit a measurable basal secretion of immunoactive SS (SSLI) which can be augmented by carbachol, acetylcholine, or oxotremorine. The EC50 for carbachol is about 1 microM. Atropine, but not hexamethonium, antagonizes the action of cholinergic agonists. Cobalt or tetrodotoxin pretreatment diminishes basal secretion and eliminates the response to carbachol. Serotonin, several serotonin agonists, and gamma-aminobutyric acid (GABA) suppress carbachol-induced secretion. The GABA blockers bicuculline or picrotoxinin reverse the effect of added GABA and by themselves also augment SSLI secretion. Picrotin is inactive. The direct response to either bicuiculline or picrotoxinin is prevented by cobalt or tetrodotoxin treatment. These observations are consistent with the presence of a muscarinic cholinergic receptor which acts by a mechanism depending on an action potential and calcium influx to enhance the release of SSLI from neurosecretory cells. The data also support the conclusion that GABAergic transmission occurs within the cultures to tonically inhibit SSLI secretion. GABAergic, cholinergic, and serotoninergic systems may thus interact at the level of the hypothalamus to modulate SS secretion in vivo and thereby influence anterior pituitary release of GH and TSH.

Animals↗