Calcitonin gene-related peptide in the human thyroid, pituitary and brain
Abstract
Alternative splicing of rat calcitonin (CT) gene transcripts resulting in the production of calcitonin gene-related peptide (CGRP) in neural tissue and of CT in the thyroid has been proposed by Rosenfeld et al. (1983b). We have recognized CGRP- and CT-like peptides in extracts of the human brain, pituitary and thyroid using a combination of gel filtration analysis and HPLC, and specific RIAs. Immunoreactive CGRP was estimated in a heterologous RIA using 125I-labelled rat CGRP as ligand and antibodies raised to the rat hormone, and human CT in a homologous RIA. The levels of CGRP and CT are measured against synthetic rat CGRP and monomeric human CT, respectively, and expressed in ng and μ g equivalents (eq). The content of immunoreactive CGRP of the neocortex (n = 3), the cerebellar cortex (n = 6), the periventricular mesencephalic region (n = 3) and the thyroid (n = 5) was similar (mean ± SE, 0.79 ± 0.16 ng eq/g wet tissue 1.51± 0.14 ng eq/g 1.84 ± 0.12 ng eq/g and 5.0 ± 0.9 ng eq/g, respectively), whereas pituitary glands (n = 21) and medullary thyroid carcinomas (n = 6) contained higher levels (31.3 ± 5.1 ng eq/g and 7.66 ± 5.42 μg eq/g, respectively). Immunoreactive CT was lowest in the neocortex, cerebellar cortex and the periventricular mesencephalon (0.31 ± 0.07 ng eq/g 0.30 ± 0.09 ng eq/g and 0.26 ± 0.09 ng eq/g, respectively), followed by the pituitary and thyroid (2.77 ± 0.62 ng eq/g and 146 ± 26 ng eq/g, respectively), and was highest in medullary thyroid carcinoma tissue (680 ± 372 μg eq/g). The identification of CGRP-like peptides in the thyroid, pituitary and brain suggests that the production of CGRP may not be organ-specific in man.
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2002, NeuropeptidesTo explore the age-related change in endothelium-dependent vasorelaxation, plasma concentrations and the expression of calcitonin gene-related peptide (CGRP) as well as serum concentrations of asymmetry dimethylarginine (ADMA), male Sprague–Dawley rats, aged 6 and 24 months were tested. The level of ADMA and CGRP in blood, and CGRP mRNA in dorsal root ganglia (DRG) were determined by high-performance liquid chromatography (HPLC), radioimmunoassay or semi-quantitative reverse-transcription polymerase chain reaction, respectively. Vasodilator responses to cumulative concentrations of acetylcholine (ACh) () and CGRP () were tested at the plateau of contraction in aortas rings. Vasodilator responses to ACh or CGRP at 24 months of age were decreased compared with 6 months. The serum concentration of ADMA at 24 months of age was significantly increased compared with 6 months, while both plasma concentrations of CGRP and the expressions of α- and β-CGRP mRNA were unchanged at two age groups. The results suggest that endothelium-dependent relaxation, but not concentrations and the expressions of CGRP, is decreased in aged rats, and the decrease in endothelium dependence of vasodilator response to CGRP may be related to the elevation of endogenous ADMA.
Calcitonin gene-related peptide-like immunoreactivity marks putative visceral sensory pathways in human brain
2000, NeuroscienceCalcitonin gene-related peptide serves as a neuromodulator in several ascending visceral sensory pathways from the parabrachial nucleus to the thalamus, amygdala and the visceral sensory cortex in rats, but these pathways have not been studied in primates. We have examined the distribution of calcitonin gene-related peptide-like immunoreactive innervation of the corresponding areas of the human brain, including the cortex, diencephalon and brainstem. We report the finding of three populations of calcitonin gene-related peptide-like immunoreactive cells that are homologous to those that have been characterized in the rat: the external lateral and external medial parabrachial subnuclei and the posterior intralaminar thalamic complex, including the subparafascicular, lateral subparafascicular and peripeduncular nuclei. In addition, scattered calcitonin gene-related peptide-like immunoreactive cells were found in the periventricular hypothalamus. Calcitonin gene-related peptide-like immunoreactive terminals were found in regions homologous to the projection areas of the external medial and external lateral parabrachial subnuclei in the rat, including the ventroposterior parvicellular nucleus of the thalamus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the insular cortex; and in the terminal field of the posterior intralaminar thalamic complex, including the amygdalo-striatal transition region and the insular cortex.
These results suggest that, similarly to other species, calcitonin gene-related peptide may also serve as a marker for ascending visceral sensory pathways in the human brain.
Evidence for calcitonin gene-related peptide-mediated ischemic preconditioning in the rat heart
1999, Regulatory PeptidesPrevious studies have suggested that calcitonin gene-related peptide (CGRP) may play an important role in the mediation of ischemic preconditioning. In the present study, we examined the release of CGRP during ischemic preconditioning and the effect of preconditioning frequency on this effect in the isolated rat heart. Thirty minutes of global ischemia and 40 min of reperfusion caused a significant cardiac dysfunction and an increase in the release of creatine kinase (CK) during reperfusion. Preconditioning with one, two or three cycles of 5-min ischemia and 5-min reperfusion caused a marked improvement of cardiac function and a decrease in the release of CK, and there was no difference in the degree of improvement among groups. The protective effects of ischemic preconditioning were abolished by the CGRP receptor antagonist CGRP8-37. A single preconditioning cycle induced a significant increase in the release of CGRP in the coronary effluent. In the hearts treated with two or three preconditioning cycles, the level of CGRP was highest in the first cycle, and was gradually decreased with increasing number of cycles of preconditioning. These results suggest that the protective effects of ischemic preconditioning are mediated by endogenous CGRP in the isolated rat heart.
Calcitonin gene-related peptide as a GH secretagogue in human and rat pituitary somatotrophs
1998, Brain ResearchTo elucidate the role of calcitonin gene-related peptide (CGRP) in regulating pituitary function, we investigated the effects of CGRP and the related peptide adrenomedullin (AdM) on the secretion of growth hormone (GH) in vitro from human pituitary adenoma cells, rat pituitary tumor (GH3) cells, and normal rat pituitary cells. In 3 of 5 human somatotroph adenomas, GH secretion was stimulated by CGRP (1–100 nM). In one case of somatotroph adenoma, GH release was observed following the addition of 10 nM GHRH and 10 nM CGRP. The addition of CGRP or AdM (1 pM–10 nM) evoked GH secretion from GH3 cells with a bell-shaped distribution curve. CGRP (100 pM) caused the maximum increase of GH secretion (172±14 (mean±S.D.)% of control). The addition of CGRP8–37, an antagonist of CGRP type 1 receptors, inhibited the stimulatory effect of AdM but did not inhibit the effect of CGRP. The addition of CGRP and AdM evoked moderate GH secretion from normal rat pituitary cells. These results suggested that CGRP is a new GH secretagogue in human and rat pituitary tumor cells.
Calcitropic peptides: Neural perspectives
1998, Comparative Biochemistry and Physiology - C Pharmacology Toxicology and EndocrinologyIn mammals and higher vertebrates, calcitropic peptides are produced by peripheral endocrine glands: the parathyroid gland (PTH), thyroid or ultimobranchial gland (calcitonin) and the anterior pituitary gland (growth hormone and prolactin). These hormones are, however, also found in the neural tissues of lower vertebrates and invertebrates that lack these endocrine organs, suggesting that neural tissue may be an ancestral site of calcitropic peptide synthesis. Indeed, the demonstration of CNS receptors for these calcitropic peptides and their induction of neurological actions suggest that these hormones arose as neuropeptides. Neural and neuroendocrine roles of some of these calcitropic hormones (calcitonin and parathyroid hormone) and related peptides (calcitonin gene related peptide, stanniocalcin and parathyroid hormone related peptide) are thus the focus of this review.
Role of calcitonin gene-related peptide in the vascular system on the development of the hyperdynamic circulation in conscious cirrhotic rats
1997, Journal of HepatologyBackground/Aims: Calcitonin gene-related peptide (CGRP), a potent vasodilator, plays an important role in modulating vascular tone, acting as a noncholinergic nonadrenegic neurotransmitter. The aim of this study was to assess the role of CGRP, present in the vascular system, in the developent of the hyperdynamic circulation observed in liver cirrhosis.
Methods: Two does of human α-CGRP [8–37], a specific antagonist of CGRP, were administered to cirrhotic and control rats. Hemodynamics were evaluated using radioactive microspheres in conscious animals. To investigate the arterial depressor effect of exogenous CGRP, we constructed a dose-response curve for mean arterial pressure in cirrhotic and control rats by administering human α-CGRP.
Results: The administration of high-dose human α-CGRP [8–37] (300 nmol · kg body weight−1 · min−1) significantly increased both the mean arterial pressure (21±2 vs. 13±1%, p<0.01) and total vascular resistance (76±5 vs. 54±5%, p<0.01) in cirrhotic rats, compared to control rats. The splanchnic hemodynamic effects induced by human α-CGRP [8–37] were a significant decrease in percent change of portal venous inflow −42±3 vs −33±3%, p<0.05) and a significant increase in percent change of splanchnic arterial resistance (110±9 vs 76±55, p<0.01) in cirrhotic rats, compared to control rats. Low-dose human α-CGRP [8–37] (60 nmol · kg body weight−1 · min−1) caused was much less than for the high-dose administration. The vascular response to human α-CGRP was significantly reduced in cirrhotic rats as compared to controls (ANOVA, p<0.01). Plasma concentrations of CGRP were significantly elevated in cirrhotic rats.
Conclusions: CGRP in the vascular system was involved in the modulation of vasodilation in rats with liver cirrhosis, as demonstrated by the administration of a selective CGRP antagonist and exogenous CGRP.