Bombesin affects the central nervous system to produce hyperglycemia in rats.
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Animals↗
Biomedical subjects
W W Vale
Publications and source records attributed to W W Vale.
Analogues of luteinizing hormone releasing factor modified at positions 2, 6, and 10.
Eighteen analogues of luteinizing hormone releasing factor (LRF, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) were synthesized. The ten agonistic analogues were [D-Lys6], [D-Orn6], [D-Lys6,des-Gly10,Pro9-NHEt], [D-Orn6,-des-Gly10,Pro9-NHEt]-LRF plus their respective lauric acid conjugates as well as [(Nepsilon-Ac)-D-Lys6] and [(Ndelta-Ac)-D-Orn6]-LRF. The eight antagonistic analogues were [des-His2,D-Lys6], [des-His2,D-Orn6], [des-His2,D-Lys6,des-Gly10,Pro9-NHEt], [des-His2,D-Orn6,des-Gly10,Pro9-NHEt]-LRF as well as their respective lauric acid conjugates. Biological activities of these analogues were determined in vitro, using LRF as the standard for the agonists and [des-His2,D-Ala6]-LRF for the antagonists. The potency of the agonists ranged from 1 to 17 times the activity of LRF while the antagonists had between 1 and 3 times the potency of [des-His2,D-Ala6]-LRF.
Animals↗
Tyrosylated analogues of somatostatin.
The total synthesis of [tyr1]-, [tyr6]-, E1Tyr7], [d-tyr8]-, [tyr11]-,and [tyr1,D-Trp8]somatostatin is described. The biological potencies of these analogues in vitro (inhibition of spontaneous secretion of radioimmunoassayable growth hormone by cultured rat anterior pituitary cells) as compared with that of somatostatin (100) were found to be 116, 29, 108, 10, 65, and 400, respectively; in vivo, in the rat, these peptides were assayed for their ability to inhibit the spontaneous release of insulin and glucagon. No statistically significant discrepancies were observed in the potency values obtained in vitro and in vivo further indicating similarities of specificities and sensitivities of the pituitary and pancreatotropic receptors.
Animals↗
In vitro plasma inactivation of thyrotropin releasing factor (TRF) and related peptides. Its inhibition by various means and by the synthetic dipeptide PCA-His-OME.
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Animals↗
Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing.
Alternative processing of the RNA transcribed from the calcitonin gene appears to result in the production of a messenger RNA in neural tissue distinct from that in thyroidal 'C' cells. The thyroid mRNA encodes a precursor to the hormone calcitonin whereas that in neural tissues generates a novel neuropeptide, referred to as calcitonin gene-related peptide (CGRP). The distribution of CGRP-producing cells and pathways in the brain and other tissues suggests functions for the peptide in nociception, ingestive behaviour and modulation of the autonomic and endocrine systems. The approach described here permits the application of recombinant DNA technology to analyses of complex neurobiological systems in the absence of prior structural or biological information.
Amino Acid Sequence↗
Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide.
Alternative splicing of RNA transcripts from the calcitonin gene produces mRNAs that encode different polypeptides. While the mRNA encoding calcitonin predominates in thyroidal 'C' cells, calcitonin gene-related peptide (CGRP) mRNA appears to be the major mRNA component in non-thyroid tissue, including brain. The predicted peptide arising from translation of CGRP mRNA has now been identified immunocytochemically throughout the central and peripheral nervous systems. CGRP, a 37-residue peptide, is distributed in brain pathways subserving sensory, motor and autonomic functions. We report here that CGRP acts in the central nervous system to stimulate selectively noradrenergic sympathetic outflow.
Animals↗
Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells.
Calcitonin gene-related peptide (CGRP) is a putative novel neuropeptide predicted on the basis of alternative RNA processing events of primary transcripts of the calcitonin gene. Distinct mRNAs encoding either calcitonin or CGRP are generated from the calcitonin gene RNA transcript in what appears to be a tissue-specific manner. The predicted peptide has now been detected immunocytochemically in discrete regions of the central and peripheral nervous systems and potent in vivo actions have been reported for centrally and peripherally administered synthetic CGRP. However, so far there is no evidence that CGRP is secreted or released by intact cells. The present experiments investigated the possible secretion of CGRP in vitro using primary dispersed cell cultures of the adult rat trigeminal ganglion, which previously has been found to contain large amounts of CGRP mRNA (ref. 2). We report here that immunoreactive CGRP is spontaneously released by cultured trigeminal ganglion cells and that secretion is stimulated by incubation in high potassium medium in a calcium-dependent fashion. Chromatographic characterization of the secreted CGRP-like immunoreactivity (CGRP-LI) isolated only one molecular form which appears to be similar or identical to the predicted rat CGRP (1-37).
Animals↗
Independent effects of growth hormone releasing factor on growth hormone release and gene transcription.
The synthesis and secretion of growth hormone (GH) by the somatotropic cells of the anterior pituitary is under complex hormonal regulation. The hypothalamic peptides, growth hormone releasing factor (GHRF) and somatostatin, respectively stimulate and block GH release. We have shown that treatment of primary cultures of rat anterior pituitary cells with GHRF stimulates transcription of the GH gene, as well as GH release, and that this reflects the response of pituitary cells in vivo. Gick et al. have shown a stimulation of GH mRNA levels in normal pituitary cells in response to GHRF. Because normal pituitary cells are the physiological target for GHRF and because they exhibit both transcriptional and release responses to the hormone, they provide a valuable system with which to examine the important possibility of a link between hormone synthesis and release in secretory cells. Using this system, we demonstrate here that GHRF stimulates GH gene transcription independently of GH release and, conversely, that other agents can stimulate GH release without affecting transcription of the GH gene.
Animals↗
Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease.
Alzheimer's disease is a progressive degenerative disease of the nervous system characterized neuropathologically by the presence of senile plaques and neurofibrillary tangles in amygdala, hippocampus and neocortex. Dysfunction and death of basal forebrain cholinergic neurones projecting to forebrain targets are associated with marked decreases in cholinergic markers, including the activity of choline acetyltransferase (ChAT). Although cortical levels of somatostatin and somatostatin receptors are reduced in Alzheimer's, no consistent changes have been reported in other neuropeptide systems. We have now examined in control and Alzheimer's brain tissues pre- and postsynaptic markers of corticotropin-releasing factor (CRF), a hypothalamic peptide regulating pituitary-adrenocortical secretion which also seems to act as a neurotransmitter in the central nervous system (CNS). We have found that in Alzheimer's, the concentrations of CRF-like immunoreactivity (CRF-IR) are reduced and that there are reciprocal increases in CRF receptor binding in affected cortical areas. These changes are significantly correlated with decrements in ChAT activity. Our results strongly support a neurotransmitter role for CRF in brain and demonstrate, for the first time, a modulation of CNS CRF receptors associated with altered CRF content. These observations further suggest a possible role for CRF in the pathophysiology of the dementia. Future therapies directed at increasing CRF levels in brain may prove useful for treatment.
Aged↗
Comparative effects of two different delivery systems on gonadotropin-releasing hormone (GnRH) antagonist-induced suppression of gonadotropins and testosterone in man.
The Nal-Glu gonadotropin-releasing hormone (GnRH) antagonist, when given in daily subcutaneous (SC) doses of 5 mg or higher, maximally suppresses serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to near undetectable levels and induces azoospermia in normal men; lower doses (1.5 and 3.0 mg) are less effective. Cost and convenience are important considerations in contraceptive development. Studies with GnRH agonists suggest that constant delivery is more effective in suppressing gonadal function than equal doses by single daily injection. In this study, we examined whether the constant infusion (CI) of a submaximal suppressive dose (1.5 mg) of Nal-Glu would be more effective in suppressing the pituitary-gonadal axis than its repeated single daily injections (SDI). This (1.5 mg) dose was selected because the 5 mg dose given once daily SC for 21 days led to maximal suppression of LH, FSH, and testosterone (T) levels, whereas 1.5 mg once daily for 21 days gave only partial suppression. It was felt that if continuous infusion was considerably more effective than intermittent administration of this submaximal dose, then the development of long-acting sustained release delivery systems for contraceptives based on GnRH antagonist analogs would allow both reduced cost and enhanced convenience. One and a half mg of Nal-Glu was administered SC either as a SDI or CI over 24 hours for 21 days to two groups of five normal men. Three measurements of serum LH, FSH, and T were performed before antagonist injection and 1, 2, 4, 8, 12, 16, and 24 hours after Nal-Glu injection on days 0, 1, 7, 21.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗