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W W Vale

Publications and source records attributed to W W Vale.

At least 145 records · Page 8Linked to original sources
PubMed1987

Corticotropin-releasing factor as a transmitter in the human olivocerebellar pathway.

This study demonstrates that the neuropeptide, corticotropin-releasing factor (CRF), is present in neurons of the human inferior olivary complex (IOC). The medulla (including the inferior olive) and the anterior vermis of the cerebellum of 6 human controls obtained at autopsy were immunostained with an antibody directed against CRF. CRF receptors in cerebellum were localized with labeled CRF using in vitro receptor autoradiography. The great majority of neurons in all divisions of the IOC expressed CRF immunoreactivity, and CRF-immunoreactive fibers were demonstrated in the hilus of the olive and in the molecular layer of the cerebellum, where they closely resembled climbing fibers as visualized with other methods. CRF receptors were enriched in the cerebellum, with the highest density in inner portions of the molecular layer. These findings in human brain, consistent with studies in tissues from rat, cat, and monkey, demonstrate that CRF may be a peptidergic transmitter in the IOC climbing fiber system and that CRF receptors are expressed by cellular targets in the cerebellum.

Adult↗
PubMed1987

Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease.

In the brains of controls and individuals with Alzheimer's disease (AD), antisera to corticotropin-releasing factor (CRF) were used to immunostain neurons and their processes. In AD, we identified abnormal CRF-immunoreactive axons as well as neurites associated with deposits of amyloid in brain regions showing senile plaques. The number of immunoreactive fibers was decreased in individuals with AD. In contrast, CRF immunoreactivity was markedly increased in some neurons located within the paraventricular nucleus (PVN) of the hypothalamus. These findings support previous neurochemical studies indicating that certain CRF systems are affected in AD.

Adult↗
PubMed1987

Brain distribution of radioimmunoassayable gonadotropin-releasing hormone in female goldfish: seasonal variation and periovulatory changes.

A radioimmunoassay (RIA) for [Trp7, Leu8]gonadotropin-releasing hormone (sGnRH) was developed to determine the gonadotropin-releasing hormone (GnRH) content in discrete brain areas of female goldfish at different stages of ovarian development. Temporal changes in serum gonadotropin (GtH) and GnRH concentrations in discrete brain areas were measured during spontaneous ovulation. There were no clear parallel changes in brain GnRH with seasonal ovarian development in goldfish. However, under a 10 degrees temperature acclimation regimen, the GnRH content in the hypothalamus and pituitary decreased as the ovary progressed from the regressed to the mature condition; on the other hand. GnRH content in the spinal cord increased in sexually mature fish compared with that in regressed fish. Significant decreases in GnRH concentration were observed in certain brain areas (olfactory bulbs, telencephalon, hypothalamus, and pituitary) of fish undergoing spontaneous ovulation compared with those of nonovulatory fish. The simultaneous changes of GnRH concentration in these brain areas suggested that the GnRH neuronal system may function as an integrated unit for the activation of GtH secretion during ovulation in goldfish.

Animals↗
PubMed1987

Characterization of gonadotropin-releasing hormone (GnRH) binding to pituitary receptors in goldfish (Carassius auratus).

Goldfish pituitary gonadotropin-releasing hormone (GnRH) receptors were characterized by using a superagonist analog of teleost GnRH (tGnRH-A; [D-Arg6, Trp7, Leu8, Pro9-NHEt]-GnRH). Equilibrium binding of 125I-tGnRH-A to a goldfish pituitary membrane preparation was achieved after a 30-min incubation at 4 degrees C; binding was significantly reduced after increasing incubation temperature to 22 degrees C. Binding of the radioligand was a function of tissue concentration, with a linear correlation over the range of 0.5-2 pituitary per tube. Incubation of the pituitary membrane preparation with increasing concentrations of 125I-tGnRH-A indicated saturable binding at radioligand concentrations of 470 pM and above. The binding of 125I-tGnRH-A was found to be reversible after addition of the cold analog, and the dissociation curve could be resolved into two linear components; slower rates of dissociation of 125I-tGnRH-A were observed after the addition of excess unlabeled tGnRH than after the addition of tGnRH-A, indicating that the analog is more effective in displacing the label than the native peptide. Addition of the cold analog displaced bound 125I-GnRH-A, and Scatchard analysis suggested the presence of at least two classes of binding sites: a high-affinity/low-capacity site and a low-affinity/high-capacity site. Bound 125I-GnRH-A was displaced by tGnRH from both sites in parallel to that observed with tGnRH-A, indicating that both peptides bind to the same classes of binding sites; however, tGnRH-A had a greater affinity for the receptors than the native tGnRH. These results demonstrated the presence and provided characterization of GnRH receptors in goldfish pituitary.

Animals↗
PubMed1987

Abnormalities in corticotropin-releasing hormone (CRH) in Alzheimer's disease and other human disorders.

CRH-IR is significantly reduced in the cerebral cortex of individuals with AD, PD and PSP. Furthermore, we report that the decreases in CRH-IR in AD are accompanied by reciprocal increases in CRH receptors in affected cortical areas. The changes in pre- and postsynaptic markers for CRH are significantly correlated with decrements in ChAT activity. The demonstration of an up regulation of CRH receptors following a decrease in CRH-IR indicates a physiological relevance of the receptor site and is consistent with the concept that CRH acts as a neurotransmitter in normal cortical functions and that disease of this peptidergic systems may be important in certain clinical manifestations of dementia. While the clinical consequences of the changes in CRH in these various disorders are unclear, future therapies directed at increasing CRH levels in brain may prove useful for treatment.

Acetylcholine↗
PubMed1987

Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man.

The role of the dopaminergic system and its interaction with GH-releasing hormone (GHRH) in the regulation of GH secretion was investigated in normal men in two complementary studies. The men were given continuous iv infusions of 0.15 M saline (5 h), dopamine (4 micrograms/kg X min; 1 h), GHRH (2 ng/kg X min; 2 h), and GHRH (2 ng/kg X min; 2 h) plus dopamine (4 micrograms/kg X min; 1 h) on four separate occasions, and serum GH responses were measured. In a second study, on separate days, placebo or bromocriptine (2.5 mg/dose) was administered, and GH and PRL responses to a single iv GHRH dose were measured. A continuous infusion of dopamine and GHRH on separate days stimulated GH secretion in all subjects. The mean integrated GH secretion was 13.2 +/- 3.1 (+/- SEM) ng/mL X h during the dopamine infusion and 14.7 +/- 4.6 during GHRH, compared with 1.7 +/- 0.4 during the saline infusion. The combination of GHRH and dopamine resulted in the greatest stimulation of GH secretion (29.8 +/- 5.7 ng/ml X h; P less than 0.05 vs. 3 other study days). The oral dopamine agonist bromocriptine also augmented GHRH-stimulated GH secretion. Integrated GH secretion after a single iv injection of GHRH following two doses of bromocriptine was 160 +/- 29.5 ng/ml X h compared with 81.3 +/- 22.2 after placebo (P = 0.04). We suggest that these findings are compatible with the hypothesis that dopamine inhibits hypothalamic somatostatin secretion, which then allows for a greater stimulatory effect of GHRH.

Adult↗
PubMed1987

Differential activation of type I and type II 3',5'-cyclic adenosine monophosphate-dependent protein kinases by growth hormone-releasing factor.

Rat GH-releasing factor (rGRF) stimulated GH release and intracellular cAMP accumulation in cultured rat anterior pituitary cells with EC50 values of approximately 10 and 150 pm, respectively. Consistent with an effect on cellular cAMP levels, rGRF stimulated the adenylate cyclase activity of rat anterior pituitary membranes with an EC50 value of approximately 60 pm. Using antisera directed against the regulatory subunits of type I and II cAMP-dependent protein kinases, these enzymes were immunoprecipitated from the cytosolic fraction of cultured cells in order to monitor the degree of their activation by rGRF. Both isoenzymes were rapidly activated in cells incubated with rGRF but with different kinetics; full activation of protein kinase I was evident within 3-5 min and activation of protein kinase II occurred between 5 and 15 min. The magnitude of activation was differentially regulated by rGRF in a concentration-dependent manner. Somatostatin only partially attenuated rGRF-stimulated GH release, cAMP accumulation, and adenylate cyclase activation. Somatostatin was effective in partially antagonizing activation of protein kinase II at all concentrations of rGRF and of protein kinase I only at intermediate concentrations of rGRF. The significance of this rGRF-induced differential activation of the two isoenzymes of cAMP-dependent protein kinase is discussed in terms of the multiple effects of rGRF on somatotropic cells of the rat anterior pituitary.

Animals↗
PubMed1987

The cellular actions of vasopressin on corticotrophs of the anterior pituitary: resistance to glucocorticoid action.

The cellular actions of vasopressin (AVP) in the anterior pituitary were investigated. HPLC analysis of [3H]inositol-labeled cells indicated that AVP stimulated a rapid increase in inositol-1,4,5 trisphosphate (IP3), inositol-1,4 bisphosphate, and inositol-4 monophosphate levels. While CRF had no effect on basal IP3 levels, it blocked their stimulation by AVP. CRF-stimulated ACTH secretion and cAMP accumulation were potentiated by AVP. AFter dexamethasone (DEX) treatment (20 nM, 18 h), CRF-dependent ACTH secretion and cAMP accumulation were attenuated but AVP was still able to potentiate both of these actions of CRF suggesting that cellular actions of AVP may be resistant to DEX effects. Therefore, [3H]AVP binding was determined in control and DEX-treated cells. Pretreatment with DEX had no effect on either AVP receptor affinity or on the number of available binding sites. Consistently, stimulation of IP3 production by AVP in DEX-treated cells was comparable to that of control cells. Protein kinase C activators such as 12-O-tetradecanoyl-phorbol-13-acetate and dioctanoylglycerol were either near additive with CRF or also potentiated the action of CRF on ACTH secretion, respectively, even after DEX pretreatment. These results indicate that, in the anterior pituitary, distinct intracellular signaling pathways mediate the actions of CRF and AVP; cAMP mediates CRF actions and IP3/protein kinase C mediate the effects of AVP. Neuromodulation of ACTH secretion by dual effector mechanisms which exhibit a complex mode of interaction and only one of which is negatively influenced by glucocorticoids, provides these cells a mechanisms by which appropriate responses can be elicited under various physiological states.

Animals↗
PubMed1987

Phorbol ester-induced down-regulation of protein kinase C abolishes vasopressin-mediated responses in rat anterior pituitary cells.

The role of protein kinase C (PKC) in the multihormonally regulated ACTH secretory responses of rat anterior pituitary cells was examined in control cells or after pretreatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of PKC. Using affinity-purified polyclonal antiserum raised against purified rat brain PKC, immunoprecipitable PKC was demonstrated in [35S]methionine-labeled cells appearing as a doublet of 78/80 kilodaltons. Long-term treatment (24 h) of cells with 0.6 microM TPA caused the specific loss of immunologically reactive PKC. Consistently, TPA pretreatment decreased the amount of phosphatidylserine-dependent protein kinase activity measured in vitro by 90%. In control cells, vasopressin (AVP) stimulated ACTH secretion and potentiated ACTH secretion stimulated by CRF. After a 24-h treatment with 0.6 microM TPA, secretory responses to AVP and the potentiating effect of AVP on CRF action were completely abolished. In contrast, CRF action on ACTH secretion, thought to be mediated by cAMP, was unaffected. Similarly, forskolin- and 8 bromo-cAMP-induced ACTH secretion remained unchanged after TPA pretreatment. These results indicate a crucial role for PKC in mediating the effects of AVP on ACTH secretion and on the potentiating action of AVP on CRF-induced secretion from corticotropic cells of the anterior pituitary.

Animals↗
PubMed1987

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy.

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.

Aged↗
PubMed1986

Local anesthetics inhibit veratridine-induced secretion of calcitonin gene-related peptide (CGRP) from cultured rat trigeminal ganglion cells.

Secretion of calcitonin gene-related peptide (CGRP) was studied with the model system of dispersed adult rat trigeminal ganglion cells. Veratridine stimulated secretion of CGRP immunoreactivity. Tetrodotoxin and local anesthetics inhibited veratridine-stimulated peptide secretion. These observations implicate sodium channels in CGRP secretion and are consistent with a role for the peptide as an extracellular neuromodulator in the sensory nervous system.

Anesthetics, Local↗
PubMed1986

A reinvestigation of the Gn-RH (gonadotrophin-releasing hormone) systems in the goldfish brain using antibodies to salmon Gn-RH.

The organization of Gn-RH systems in the brain of teleosts has been investigated previously by immunohistochemistry using antibodies against the mammalian decapeptide which differs from the teleostean factor. Here, we report the distribution of immunoreactive Gn-RH in the brain of goldfish using antibodies against synthetic teleost peptide. Immunoreactive structures are found along a column extending from the rostral olfactory bulbs to the pituitary stalk. Cell bodies are observed within the olfactory nerves and bulbs, along the ventromedial telencephalon, the ventrolateral preoptic area and the latero-basal hypothalamus. Large perikarya are detected in the dorsal midbrain tegmentum, immediately caudal to the posterior commissure. A prominent pathway was traced from the cells located in the olfactory nerves through the medial olfactory tract and along all the perikarya described above to the pituitary stalk. In the pituitary, projections are restricted to the proximal pars distalis. A second immunoreactive pathway ascends more dorsally in the telencephalon and arches to the periventricular regions of the diencephalon. Part of this pathway forms a periventricular network in the dorsal and posterior hypothalamus, whereas other projections continue caudally to the medulla oblongata and the spinal cord. Lesions of the ventral preoptic area demonstrate that most of the fibers detected in the pituitary originate from the preoptic region.

Animals↗
PubMed1986

Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide.

A series of experiments was performed to investigate the effects of corticotropin-releasing factor (CRF) on the amplitude of the acoustic startle response (ASR) in rats. Intracerebroventricular (ICV) administration of 1 microgram rat CRF significantly potentiated acoustic startle amplitude; these effects were reversed in a dose-dependent manner by pretreatment with the benzodiazepine chlordiazepoxide (CDP). Doses of CDP that antagonized CRF-potentiated ASR did not lower startle baseline or antagonize amphetamine- or strychnine-potentiated ASR. These results suggest that CRF has "anxiogenic" properties and may serve as a neuroendocrine modulator of stress-enhanced behaviors.

Acoustic Stimulation↗
PubMed1986

New effective gonadotropin releasing hormone antagonists with minimal potency for histamine release in vitro.

In order to minimize the adverse effect of histamine release in the rat of some gonadotropin releasing hormone (GnRH) antagonists, such as [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH, new structures with modifications at positions 1, 2, 3, 5, 6, 7, and 10 were synthesized and tested in several biological systems. In vitro: the affinity for the pituitary GnRH receptor was measured as was the ability of the analogues to inhibit GnRH-stimulated release of luteinizing hormone (LH) by dispersed anterior pituitary cells in culture and to release histamine from rat mast cells. In vivo: inhibition of ovulation in the cycling rat was determined after subcutaneous (sc) injection of the peptides at noon on the day of proestrus; the duration of action of the peptides was evaluated by measuring LH levels in the castrated male rat after sc injection of some selected analogues. [Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,D-4-p-methoxy benzoyl-2-aminobutyric acid6,DAla10]-GnRH was found to be one of the most potent analogues of this series, causing a 100% inhibition of ovulation at 5 micrograms/kg or less. Release of histamine was observed at doses 10-25 times that required for [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH. Thus, introduction of arginine in position 5 with a hydrophobic amino acid in position 6 is compatible with high potency in several biological systems and results in compounds with lowered potency to release histamine compared to homologous peptides with tyrosine in position 5 and D-arginine in position 6.

Animals↗
PubMed1986

Coexistence of tyrosine hydroxylase and growth hormone-releasing factor in a subpopulation of tubero-infundibular neurons of the rat.

The distribution of growth hormone-releasing factor (GRF) and tyrosine hydroxylase (TH), a marker for dopamine neurons in this region, was analyzed in the mediobasal hypothalamus with indirect immunofluorescence histochemistry and an elution-restaining procedure. TH-like immunoreactivity was present in most GRF-immunoreactive cells in the ventral part of the arcuate nucleus (ventral A12 dopamine cell group). Dopamine cells in the dorsal A12 group and, for example, in the hypothalamic A14 cell group seemed to lack GRF peptide. Partly overlapping GRF- and TH-immunoreactive fibers in the median eminence were observed, indicating possible coexistence of the two compounds also in nerve endings close to portal vessels. These findings suggest that a subpopulation of A12 dopamine neurons produces, stores and releases a GRF-like peptide. Possible interactions of GRF and dopamine in the control of growth hormone secretion are discussed.

Animals↗
PubMed1986

Corticotropin-releasing factor binding to the anterior pituitary receptor is modulated by divalent cations and guanyl nucleotides.

The binding of ovine CRF to bovine anterior pituitary membranes was characterized with the radioligand [Nle21, m-125I Tyr32]ovine CRF. The specific binding of CRF was increased by millimolar concentrations of the divalent cations Mg2+, Ca2+, and Mn2+, but was unaffected by the monovalent cations Na+, Ki+, and Li+. The increase in specific binding was not caused by a change in the affinity, but resulted from an apparent increased number of high affinity binding sites. In the presence of 10 mM Mg2+, CRF binding was saturable, specific, and of high affinity. At room temperature, under optimum conditions, binding reached equilibrium within 70 min, remained stable for at least 4 h, was reversible by excess unlabeled peptide, and was characterized by a Kd of 1.3 nM (0.74-2.4) and a total number of sites, R degree, of 90 fmol/mg protein (55-145). The affinity for the bovine membranes was the same as that for rat anterior pituitary membrane homogenates, and the concentrations of sites were similar. The relative binding affinities for the CRF receptor of selected agonists and antagonists in the bovine and rat systems were similar, and both showed good correlation with the relative in vitro potencies at stimulating or antagonizing, respectively, ACTH release from cultured rat anterior pituitary cells. The nonhydrolyzable GTP analog 5'-guanylylimidodiphosphate [Gpp(NH)p], caused a dose-dependent inhibition of bound radioligand, with an EC50 of about 0.5 microM. In the presence of 1 microM Gpp(NH)p, the number of high affinity CRF-binding sites was reduced, but the affinity was unchanged. In the presence of 5 microM Gpp(NH)p, there was no detectable high affinity binding, and the rate of dissociation of previously bound radioligand was increased. The other guanyl nucleotides, GTP and GDP, inhibited binding but to a lesser extent, whereas GMP and (Bu)2cGMP were ineffective. The inhibition was specific for guanyl nucleotides. In view of the established effects of guanyl nucleotides and divalent cations on adenylate cyclase-linked receptors, these data support the involvement of the adenylate cyclase system in the mechanism of action of CRF on the anterior pituitary.

Adenylyl Cyclases↗
PubMed1986

Central administration of corticotropin-releasing factor modulates oxytocin secretion in the rat.

Recently, it has been reported that oxytocin (OT), classically known for its function during parturition and lactation, is secreted in response to stressful stimuli in male rats. In these and in the present report it was found that swimming stress, restraint stress, ether stress, and footshock stress elevate OT secretion without affecting arginine-vasopressin (AVP) secretion. In the present studies, we investigated the possible modulation of OT secretion by CRF which is known to be released during stress. Male and female rats received intraventricular (icv) injections of 0.75 nmol (5 micrograms) rat CRF and were killed 5 min after the treatment. CRF significantly elevated OT secretion in male and female rats 3.4- and 4-fold, respectively. Plasma AVP levels were not affected by the treatment. The effect of CRF on OT release was structure specific since rat CRF, ovine CRF, and sauvagine were equipotent releasers of OT while an inactive analog to CRF, ovine CRF did not change plasma OT levels. In another set of experiments rats were pretreated with either CRF-antiserum (0.5 ml iv) or dexamethasone (20 micrograms/rat ip) and then injected with icv CRF. Both CRF-antiserum and dexamethasone blocked the rise in ACTH release after icv CRF completely but did not influence the OT response. This suggests CRF may be acting centrally but not at the level of the neurohypophysis to change OT secretion. Since parvocellular but not magnocellular neurons of the paraventricular nucleus have been demonstrated to be steroid sensitive in immunohistochemical studies, we suggest CRF may act directly or indirectly upon magnocellular neurons to increase OT release. Intravenous administration of 0.75 nmol CRF increased both OT and AVP levels in peripheral blood. The magnitude of this increase was similar (2- to 4-fold stimulation) to responses after icv administration of CRF. Intravenous administration of CRF results in hypotension and may therefore cause a baroreceptor mediated release of AVP and OT. From the above evidence we conclude: physical and mental stresses which do not result in changes in blood volume or osmolality evoke an increase in OT secretion while AVP secretion remains unchanged; CRF administered icv mimics OT responses observed after ether stress or footshock stress; CRF may play a role in regulating stress-induced OT secretion in the rat.

Adrenocorticotropic Hormone↗