Search PubMed⌕ Search

Biomedical subjects

W Vale

Publications and source records attributed to W Vale.

At least 217 records · Page 12Linked to original sources
PubMed1987

Identification and characterization of a pituitary corticotropin-releasing factor binding protein by chemical cross-linking.

A corticotropin-releasing factor (CRF) binding protein has been identified based on the chemical cross-linking of ovine [Nle21,m-125I-Tyr32]CRF (125I-oCRF) to bovine anterior pituitary membranes using disuccinimidyl suberate (DSS). The apparent molecular weight of the cross-linked complex determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography was approximately 75,000 and was slightly decreased in its nonreduced state, suggesting the presence of intramolecular disulfide bonds. Subtracting the molecular weight of 125I-oCRF, the binding protein appeared to have a molecular weight of approximately 70,000. The cross-linking was specific since an excess (1 microM) of an unrelated peptide (insulin) did not affect the appearance of the Mr 75,000 band. The concentration of CRF required to inhibit cross-linking by 50% was found to be similar to that determined for bovine pituitary CRF receptors by radioreceptor assay. The nonhydrolyzable GTP analogue 5'-guanylylimidodiphosphate dose dependently inhibited the cross-linking of 125I-oCRF to the Mr 70,000 protein. 50 nM of the inactive CRF analogue, [Ala14]oCRF, had no effect on the cross-linking, an observation which is consistent with this compound's low potencies in bioassays and radioreceptor assays. These results strongly suggest that this Mr 70,000 protein is the biological bovine anterior pituitary CRF receptor.

Adrenocorticotropic Hormone↗
PubMed1987

An endogenous ligand of the brain sigma/PCP receptor antagonizes NMDA-induced neurotransmitter release.

The present study provides evidence for the presence of an endogenous ligand for the phencyclidine (PCP) receptor of mammalian brain. Partially purified bovine hippocampal extracts potently and dose dependently inhibit binding to PCP receptors of [3H]N-(1-[2-thienyl]-cyclohexyl)piperidine (TCP), a highly potent and specific ligand of PCP receptors. In addition to demonstrating PCP-like binding properties, the partially purified extract mimics biological actions of PCP upon neurotransmitter release. HPLC fractions active in the [3]TCP binding assay, by contrast to fractions inactive in the binding assay, potently elicited stimulation of spontaneous acetylcholine and dopamine efflux and inhibited NMDA-stimulated release of acetylcholine and dopamine. The transmitter release assay provides validation of a PCP-like physiological activity exerted by bovine hippocampal extracts partially purified by HPLC.

Acetylcholine↗
PubMed1987

Localization, secretion, and action of inhibin in human placenta.

Inhibin is a gonadal glycoprotein hormone that regulates the production of follicle-stimulating hormone (FSH) by the anterior pituitary gland and exhibits intragonadal actions as well. The present study shows that inhibin-like immunoreactivity (inhibin-LI) is present in cells of the cytotrophoblast layer of human placenta at term and in primary cultures of human trophoblasts. Human chorionic gonadotropin (hCG) stimulated secretion of inhibin-LI from these cultured placental cells. This effect was mimicked by 8-bromo-cyclic adenosine monophosphate (8-bromo-cAMP), forskolin, and cholera toxin, suggesting that the mechanism of hCG induction of placental inhibin-LI secretion is cAMP-dependent. Incubation with an antiserum that binds the alpha-subunit of human inhibin increased the secretion of hCG and gonadotropin-releasing hormone-like immunoreactivity (GnRH-LI) from trophoblast cells in culture, suggesting a local tonic inhibitory action of endogenous inhibin on hCG and GnRH-LI release. The action of inhibin on hCG secretion may partially require the presence of placental GnRH, as suggested by evidence that a synthetic GnRH antagonist partially reverses the hCG increase induced by inhibin immunoneutralization. Results suggest paracrine roles for both inhibin and GnRH in the regulation of placental hCG production.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Behavioral activation by CRF: evidence for the involvement of the ventral forebrain.

Rats injected intracerebroventricularly with corticotropin releasing factor (CRF) at the level of the lateral ventricle or cisterna magna showed a dose-dependent increase in locomotor activity. The increase in locomotor activity from injections of CRF into the cisterna magna was blocked by a cold cream plug in the cerebral aqueduct. An identical plug failed to block the increase in locomotor activity produced by CRF injected into the lateral ventricle. Intracerebral injections of CRF produced a site specific increase in locomotor activity with the largest increases observed from CRF injected into the substantia innominata/lateral preoptic area. Results suggest that the locomotor activating effects of CRF may be due to an activation of CRF receptors in the ventral forebrain, a region rich in CRF cell bodies and projections.

Animals↗
PubMed1987

Presence of glucocorticoid receptor immunoreactivity in corticotrophin releasing factor and in growth hormone releasing factor immunoreactive neurons of the rat di- and telencephalon.

By means of the indirect immunoperoxidase technique using two-color immunocytochemistry a moderate to strong nuclear glucocorticoid receptor (GR) immunoreactivity was demonstrated in the vast majority of the corticotrophin-releasing factor (CRF)-immunoreactive nerve cells of the parvocellular parts of the paraventricular hypothalamic nucleus, of the septohypothalamic nucleus, of the bed nucleus striae terminalis and of the central and medial amygdaloid nuclei. All the growth hormone-releasing factor (GRF)-immunoreactive nerve cells of the lateral magnocellular part of the arcuate nucleus in its entire rostrocaudal extent showed a moderate GR immunoreactivity. These results and others indicate that glucocorticoids may directly affect all the CRF and GRF cell populations projecting into the median eminence as well as CRF and GRF neurons controlling behavioral and autonomic functions.

Animals↗
PubMed1987

Growth hormone and prolactin responses to bolus and sustained infusions of GRH-1-40-OH in man.

To determine whether GRH stimulates PRL secretion we studied the effects of iv bolus injections and prolonged infusions of GRH 1-40-OH on PRL and GH serum levels in normal volunteers. Eight patients with acromegaly, two of whom had elevated basal levels of PRL, were also tested with single bolus injections. Six normal subjects given 3.3 micrograms/kg bolus injections of GRH showed a mean increment of GH of 22.0 +/- 1.7 ng/ml (mean +/- SE). A small rise in PRL was noted in 5 of the 6 subjects (mean peak level of 6.4 +/- 1.9 ng/ml vs basal level of 3.3 +/- 0.4 ng/ml, p less than 0.05). During the continuous intusion of GRH (10 ng/kg/min), GH levels rose gradually from a mean baseline of 1.1 +/- 0.1 ng/ml to a mean peak of 30.0 +/- 7.2 ng/ml at about 2 h and then slowly declined to a nadir of 4.2 +/- 0.4 ng/ml at 330 min. PRL levels did not rise significantly during the infusion. To determine whether the decline in GH levels in the face of continued infusion was due to loss of GH responsiveness, a 3.3 micrograms/kg bolus of GRH was given during the nadir at 330 min; this GH increment was significantly less than that obtained by the GRH bolus injection without the infusion (12.9 +/- 3.5 ng/ml vs 22.0 +/- 1.7 ng/ml, p less than 0.05). The PRL response to the GRH bolus was the same during the infusion of GRH as before. In each of 8 acromegalic patients (including two who had initially elevated basal PRL levels) GRH led to an increase in both GH and PRL levels. PRL and GH levels spontaneously fluctuated in parallel in 4 acromegalic cases studied with repeated samples over 6 h during placebo administration. These experiments show that GRH has significant, though weak, PRF effect in normals and that it is more potent PRF in acromegalic patients. Furthermore, the effects on GH and PRL of a sustained infusion of GRH for 5 1/2 h are both qualitatively and quantitatively different. These results suggest that the GRH effect is exerted either on different pituitary receptors for GH and PRL regulation, or that the releasable pools of the two hormones have different sizes and/or turnover times.

Acromegaly↗
PubMed1987

Corticotropin-releasing factor antagonist blocks stress-induced fighting in rats.

Corticotropin-releasing factor (CRF) has been shown to have potent central nervous system-activating effects when administered intracerebroventricularly (i.c.v.). In the present experiment, this activating effect was exaggerated by use of a stress-motivated behavioral paradigm. Low doses of CRF (0.01 and 0.1 micrograms/rat) administered i.c.v. facilitated stress-induced fighting. More importantly, alpha-helical CRF-(9-41), a CRF antagonist, blocked stress-induced fighting produced by higher levels of stress. These results suggest that CRF in the central nervous system may have a role in mediating behavioral responses to stress.

Aggression↗
PubMed1987

Hormonal regulation of inhibin production by cultured Sertoli cells.

The hormonal regulation of inhibin production by cultured rat Sertoli cells was examined using a specific radioimmunoassay (RIA) which detects the N-terminal portion of the porcine inhibin alpha chain. FSH, but not hCG or prolactin caused a dose-dependent increase in inhibin production (EC50 for FSH = 2.4 ng/ml); both secreted and intracellular levels of inhibin were increased, but the secreted form represented one-half to two-thirds of the total. The FSH-stimulated production of inhibin was augmented by addition of a phosphodiesterase inhibitor, and could be mimicked by cholera toxin, forskolin, or dibutyryl cAMP, all of which are known to increase intracellular cAMP levels. Inclusion of either dihydrotestosterone or estradiol in the cultures had no effect on inhibin production, both in the presence and absence of FSH. Examination of the conditioned media from forskolin-treated Sertoli cells by gel filtration chromatography revealed a single peak of bioactive and immunoreactive inhibin, at a molecular weight of approximately 32,000, similar to that observed for the porcine and bovine follicular fluid inhibins. Thus, FSH activated the cAMP pathway to stimulate Sertoli cell production of inhibin which in turn suppresses pituitary FSH release to form a closed-loop feedback system.

Animals↗
PubMed1987

Central corticotropin-releasing factor suppresses natural killer cytotoxicity.

Corticotropin-releasing factor (CRF) administered as a single dose intraventricularly produces a dose-dependent suppression of rat splenic natural killer (NK) cell activity. Neither systemic CRF nor CRF in vitro significantly altered NK activity. The immunosuppressive effect of central CRF was antagonized by central, but not by systemic, preadministration of the CRF antagonist, alpha-helical oCRF residues 9-41. These data suggest that CRF released in the brain may have a role in the central modulation of natural killer cytotoxicity.

Animals↗
PubMed1987

Pituitary responses to synthetic corticotropin-releasing hormone: absence of modulatory effects by estrogen and progestin.

To determine if the activity of the adrenocorticotropic hormonal-adrenal axis is modulated in part by estrogens and progestins, we have compared pituitary and adrenal responses to corticotrophin-releasing hormone in normal women during the early follicular, late follicular, and midluteal phases of the menstrual cycle and in four women undergoing ovariectomy who received estradiol (E2) implants alone or in combination with oral medroxyprogesterone acetate administration. Basal adrenocorticotropic hormone and cortisol levels (9:00 AM) and responses to ovine CRH were unaffected by variations in E2 and progesterone during each phase of the menstrual cycle. In women undergoing ovariectomy who received E2 replacement therapy, basal concentrations of adrenocorticotropic hormone and cortisol (9:00 AM) and the responses to human corticotrophin-releasing hormone were not altered by administration of E2 alone or E2 with medroxyprogesterone acetate. Under these experimental conditions, our findings suggest that physiologic changes in E2 and progesterone levels during the menstrual cycle and replacement doses of estrogen and progestin commonly used clinically do not significantly influence basal adrenocorticotropic hormone and cortisol levels or responsiveness to corticotrophin-releasing hormone.

Adrenocorticotropic Hormone↗
PubMed1987

Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis.

Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.

Androgens↗
PubMed1987

Immunohistologic localization of corticotrophin-releasing hormone in human tumors.

The authors investigated formalin-fixed, paraffin-embedded human tissues for the presence of corticotrophin-releasing hormone (CRH) using the avidin-biotin-peroxidase technic. Immunopositivity was demonstrated in nontumorous hypothalami, 1 of 8 hypothalamic gangliocytomas, 3 of 9 bronchial endocrine tumors, 1 of 30 small cell lung carcinomas, 1 of 8 ileal endocrine neoplasms, 2 of 20 pancreatic endocrine tumors, 2 of 10 medullary thyroid carcinomas, and 1 of 3 small cell prostate carcinomas. Of the tumors containing immunoreactivity, most were associated with Cushing's syndrome; the ileal and thyroid tumors were not. Adrenocorticotrophic hormone was immunohistochemically localized in two bronchial and one pancreatic tumor, which contained CRH-like immunoreactivity. No CRH was detected in nontumorous extrahypothalamic tissues from which the CRH-containing tumors derived, two mediastinal endocrine carcinomas, six endocrine tumors of the stomach/duodenum/appendix, eight pheochromocytomas, one Merkel cell tumor, and 32 squamous and adenocarcinomas of the lung/gut. CRH-like immunoreactivity may be found in tumors composed of peptide-hormone-producing endocrine cells; hypersecretion of CRH by those neoplasms may be significant in the development of Cushing's syndrome.

Adolescent↗
PubMed1987

Beta-endorphin and dynorphin participate in the stress-induced release of prolactin in the rat.

In the rat, exposure to stress increases prolactin (Prl) secretion, and endogenous opioid peptides (EOP) are believed to play a role in this response. The aim of the present study was to evaluate the specific involvement of the different EOP (i.e. beta-endorphin [beta-END], dynorphin A [DYN-A], methionine-enkephalin [Met-ENK], and/or opiate receptors (i.e., mu/epsilon, kappa, delta) in the stress-related increase in circulating Prl. Rats were subjected to inescapable intermittent footshock (60 Hz, 2.5 mA, 1 s duration, 2 h) 2 h after the intracerebroventricular (i.c.v.) injection of specific antisera raised against beta-END, DYN-A or Met-ENK. In addition, selective opiate antagonists (beta h-END-[6-31], a peptide beta-END antagonist [5 nmol, i.c.v.], beta-funaltrexamine [beta-FNA], an mu 1 receptor antagonist [4.8 nmol, i.c.v.], Mr 1,452 MS and Mr 2,266 BS, two kappa-receptor antagonists [10 mg/kg body weight, i.p.], ICI 154, 129, a delta-receptor antagonist [100 nmol, i.c.v.]) were administered prior to footshock stress. Blood samples were collected through an indwelling jugular cannula. Exposure to footshock rapidly and significantly increased plasma Prl levels. This stress-induced release of Prl was reduced by both antisera against beta-END or DYN-A, as well as by pretreatment with beta h-END-(6-31), beta-FNA and kappa-receptor antagonists. Antiserum against Met-ENK and delta-antagonist were inactive. These results suggest that the activation of the two endogenous opioid systems, beta-END and DYN-A, centrally modulate the release of Prl induced by footshock stress.

Animals↗
PubMed1987

Studies of the inhibin family of hormones: a review.

While the concept of a nonsteroidal entity of gonadal origin, which specifically regulates FSH secretion, was proposed over 50 years ago, problems linked to the assay, isolation and characterization of this protein have only recently been solved. The structure of inhibin from follicular fluid origin has been established as a heterodimer consisting of two subunits (alpha and beta) linked by disulfide bridges. The development of antisera specifically directed against the N-terminus part of the alpha-chain of inhibin has allowed the measurement of plasma levels of inhibin, as well as the evaluation of the biological effect of removal of endogenous inhibin. These studies have demonstrated age-related changes in the circulating levels of inhibin in the female rat and support the hypothesis that inhibin represents an important modulator of FSH secretion in this species.

Amino Acid Sequence↗
PubMed1987

Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin-releasing hormone release into hypophysial-portal circulation.

To evaluate whether the hypothalamus is the site of action of CRF in inhibiting LH levels in female rats, we measured hypophysial-portal blood concentrations of immunoreactive GnRH (irGnRH) after the central injection of CRF. Ovine CRF (0.1, 1.0, 2.0, and 5.0 nmol) was injected intracerebroventricularly to intact rats on the afternoon of proestrus and in long term ovariectomized (OVX) rats in the presence or in absence of estradiol benzoate (OVX + EB). CRF injection decreased the amplitude of the proestrous irGnRH surge without affecting presurge levels. CRF (0.1 nmol) attenuated the afternoon irGnRH surge in OVX + EB rats; higher doses of CRF blocked this surge and decreased nonsurge irGnRH levels. No dose-related alterations of irGnRH levels were observed in OVX rats; only the highest dose of CRF was active. For comparison, plasma LH concentrations were measured after a single dose of CRF (2 nmol) in rats under the same experimental conditions. While CRF decreased LH concentrations in anesthetized proestrous and OVX + EB rats, it was inactive in OVX rats. In contrast, CRF injection in awake rats did decrease LH concentrations in all experimental conditions, suggesting that in OVX rats, the anesthetic (Saffan) used during portal blood collection affected CRF action on LH secretion. Indeed, the observation that the LH response to opiate receptor blockade with naloxone (2.5 mg/kg) in anesthetized OVX rats was different compared to that in awake rats suggested that the ineffectiveness of CRF to decrease irGnRH and LH in OVX anesthetized rats was related to the action of the anesthetic on the opioid system. The existence of a putative CRF-opioid interaction in the inhibitory control of LH secretion was supported by the effectiveness of naloxone to reverse the CRF-induced decrease in LH levels in EB-treated and untreated OVX rats. These results indicate that CRF attenuates LH secretion by a central action to inhibit irGnRH release into the hypophysial-portal circulation and that this action is independent of basal concentrations of irGnRH and/or LH. Moreover, the present results support the involvement of endogenous opioids in mediating the effect of CRF on LH secretion.

Animals↗
PubMed1987

Inhibin: measurement and role in the immature female rat.

The possible physiological significance of endogenous inhibin has been evaluated in the female rat during sexual maturation. Plasma inhibin levels measured by a specific RIA were very low, but detectable at 5 days of age, then progressively increased until day 17, when they showed an abrupt rise. This rise was concurrent with a dramatic fall in plasma FSH levels. At day 30, inhibin values were not significantly (P greater than 0.05) different from those of adult females. The immunoneutralization of endogenous inhibin had no statistically significant (P greater than 0.05) effect on plasma FSH levels in 10-day-old immature female rats, but markedly (P less than 0.01) increased them at day 20 and 30. These results suggest that endogenous inhibin plays a physiological role in modulating FSH secretion from day 20 of age in the female rat.

Aging↗
PubMed1987

Diminished responsiveness of the hypothalamic-pituitary-adrenal axis of the rat during exposure to prolonged stress: a pituitary-mediated mechanism.

Intact rats exposed to low or moderate intensity electroshocks for 3-5 h showed a marked increase in plasma ACTH levels 10 min after the beginning of the stress, followed by a decline despite continuous exposure to the stimulus. We have explored the role of steroid feedback, desensitization of the pituitary response to CRF, or changes in pituitary ACTH content in mediating this phenomenon. The following results were obtained. Exposure of adrenalectomized rats to shocks showed that removal of steroid feedback did not restore the ability of the animals to maintain elevated levels of circulating ACTH during electroshocks. To determine whether prolonged stress caused changes in pituitary sensitivity to CRF, intact rats received CRF, epinephrine, vasopressin, or phorbol ester at the end of the 3-h shock session; all secretagogues caused a significantly smaller increase in the plasma ACTH levels in intact rats subjected to low or moderate intensity shocks compared to that of control animals, which suggested that there was no specific desensitization to CRF. By contrast, pituitary responsiveness to CRF was not significantly altered in adrenalectomized rats submitted to low intensity shocks for 1-3 h; however, when moderate intensity shocks were used, adrenalectomized rats showed a blunting of the response to CRF comparable to that in intact animals. Finally, we observed a comparable decrease in the pituitary ACTH content of intact or adrenalectomized rats exposed to electroshocks; this decrease was proportional to the length and intensity of the shocks. We conclude that the inability of continuously stressed rats to maintain elevated plasma ACTH levels appears to be mediated through both the temporary decrease in a readily releasable pituitary ACTH pool and the negative feedback exerted by corticosterone.

Adrenalectomy↗