Action Of Thyrotropin-releasing Hormone Research Articles

Alterations in the frequency and shape of Ca2+ fluctuations in GH4C1 cells induced by thyrotropin-releasing hormone and Bay K 8644.

We have examined statistically the actions of thyrotropin-releasing hormone (TRH) and Bay K 8644, an L-type Ca(2+)-channel agonist, on the frequency and shape of cytosolic Ca2+ spikes in individual GH4C1 rat pituitary cells. TRH induced a brief (0-40 s) suppression of Ca2+ spikes followed by a period (40-200 s) of increased spike frequency. TRH treatment reduced the rate of rise and amplitude of Ca2+ spikes, and increased the rate of fall, relative to spontaneous spikes before treatment. TRH had no significant effect on the correlation between spike amplitude and the spike decay time constant tau, suggesting that the increased rate of fall was due to enhanced Ca2+ extrusion and not to decreased Ca(2+)-induced Ca2+ release. Bay K rapidly (t1/2 = 9-13 s) induced a 2-fold increase in the rate of rise of spikes with no change in the total rise time, leading to an increase in spike amplitude. It increased by 2-fold the fall time of spikes, as predicted solely by the previously observed relationship between spike amplitude and fall time. Bay K therefore appeared to increase the number of Ca2+ channels participating in each spike event without altering the kinetics of channel activation or deactivation, and without influencing Ca2+ extrusion. After addition of Bay K, the interval between spikes gradually (t1/2 approximately 100 s) increased, whereas the rate of rise remained constant and maximal. To explain these actions of TRH and Bay K, we postulate that a fraction of L-type Ca2+ channels are inactivated during each spike and must be re-activated in order to participate in a subsequent spike. We conclude further that the changes in spike frequency and profiles induced by these secretagogues are most consistent with a model in which TRH induces increases in both Ca2+ influx and efflux while Bay K induces a large increase in Ca2+ influx but has little effect on efflux.

Partial characterization of a thyrotropin releasing hormone-sensitive glycosyl-phosphatidylinositol in pituitary lactotrophes

Metabolic labelling experiments performed with cultured pituitary lactotrophes revealed the presence of a glycosyl-phosphatidylinositol (GPtdlns) structurally related to GPtdlns lipids isolated from other cell types as demonstrated by: (i) metabolic incorporation of [ 3H]galactose, [ 3H]glucosamine and [ 3H]inositol into the polar inositolphosphoglycan moiety (InsPG) and [ 3H]myristate and [ 3H] palmitate into the diacylglycerol (DAG) backbone of GPtdlns; (ii) sensitivity of the [ 3H]labelled GPtdlns to nitrous acid deamination and; (iii) sensitivity of GPtdlns to phosphatidylinositol (Ptdlns)-specific phospholipase C (PLC) hydrolysis. In cultured pituitary cells labelled to isotopic steady state with 10 μCi/ml of [ 3H]glucosamine, treatment with hypothalamic TRH (10 −6 M) induced a rapid and transient hydrolysis (ca. 50%) of the labelled GPtdlns. Moreover, as demonstrated in [ 3H]inositol labelled cells, treatment with thyrotropin releasing hormone (TRH) elicited the cleavage of [ 3H]GPtdlns in a similar manner, and this effect was followed by the phosphoinositide (Ptdlns, PtdInsP and PtdInsP 2) hydrolysis 30 s later. These results suggest that the phosphodiesterase cleavage of GPtdlns could be an early event implicated in TRH action in pituitary lactotrophes.

Thyrotropin-releasing hormone in treatment of intractable epilepsy: Neurochemical analysis of CSF monoamine metabolites

The efficacy of thyrotropin-releasing hormone in children with intractable epilepsy was investigated and changes in cerebrospinal fluid monoamine metabolites were analyzed. The 18 patients had either West syndrome (12 patients) or Lennox-Gastaut syndrome (6 patients), which was intractable to antiepileptic drug therapy and to adrenocorticotrophic hormone. Thyrotropin-releasing hormone-tartrate was administered for 4 weeks. Before and after the thyrotropin-releasing hormone administration, cerebrospinal fluid was collected and analyzed for 5-hydroxyindoleacetic acid, kynurenine, homovanillic acid, and 3-methoxy-4-hydroxyphenyl glycol. The patients were classified into 3 groups, based on seizure frequency and electroencephalographic effects: cessation of seizures and seizure discharges (very effective; group A), reduction of seizures and/or seizure discharges (effective; group B), and no changes in frequency of seizures or discharges (not effective; group C). There were 6 patients in group A, 3 in group B, and 9 in group C. There were no significant differences in monoamine metabolites before and after the thyrotropin-releasing hormone therapy. A trial of thyrotropin-releasing hormone for the treatment of intractable epilepsy is warranted and further study is required on the mechanism of the antiepileptic action of thyrotropin-releasing hormone.

Multiple intracellular signallings are involved in thyrotropin-releasing hormone (TRH)-induced c- fos and jun B mRNA levels in clonal prolactin cells

In mammosomatotropes GH3B6 cells, one of the primary responses to thyrotropin-releasing hormone (TRH) is the parallel induction of two proto-oncogenes, c-fos and jun B, which code for constituents of AP1 transcription factor. To better understand the mode of action of TRH and to look for possible functions of c-fos and jun B in these cells, we have investigated the role of different intracellular signals in the induction of each proto-oncogene on the one hand, and on prolactin (PRL) release and PRL gene expression on the other hand. Northern and dot-blot analyses revealed that the activation of protein kinase C (PKC)-, Ca 2+- or adenylyl cyclase-dependent pathways acutely increased both c-fos and jun B transcripts. However, a gene specific responsiveness was revealed using phorbol 12-myristate 13-acetate (TPA) and several combined treatments. The simultaneous activation of PKC and Ca 2+-dependent pathways resulted in synergistic stimulations of c-fos mRNA levels only. Consistently, ionomycin plus low doses of TPA solely reproduced the potent effect of TRH on c-fos transcripts. Data collected from TRH and TPA down-regulated cells indicated that TRH probably recruits TPA-dependent PKC isoforms for stimulating c-fos but not jun B transcripts. On the contrary, the TRH-induced stimulation of either proto-oncogene likely involves Ca 2+-dependent mechanisms because calcium agonists and the peptide exert non-additive effects. Finally, the synergistic stimulations observed in response to TRH combined with forskolin, indicate that adenylyl cyclase-dependent mechanisms are interconnected with TRH-induced proto-oncogene expression. The overall study also reveals that among the agonists tested, the dihydropyridine Bay K 8644 and forskolin only were capable to induce a long-lasting stimulation of c-fos and jun B mRNA levels, concomitant to increased levels of PRL transcripts, as does TRH. Considering that AP1 is assumed to be involved in signal transmission from the cell surface to the nucleus, it might be thus proposed that a common stimulation of c-fos and jun B gene expression is possibly involved in the activation of the PRL gene. On the other hand, the systematic coincidence between acute PRL release and proto-oncogenes expression suggest a role for c-fos and jun B in the control of genes involved in the secretory process.

Effects of Intravenous Thyrotropin- Releasing Hormone on Urethral Closure Pressure in Females with Voiding Dysfunction

The aim of this work was to investigate the effects of intravenously administered thyrotropin-releasing hormone (TRH) on the urethral closure pressure in a double-blind, placebo-controlled study. Sixteen female subjects with either bladder outlet obstruction (BOO) or detrusor underactivity were included in the study. Following randomization, 8 subjects (3 BOO, 5 detrusor underactivity) received 200 micrograms of TRH intravenously, and 8 (4 BOO, 4 detrusor underactivity) received saline (placebo). Standard fluid fill urethral pressure profilometry was performed at baseline and 2, 3, 5, 10, 15, and 20 min following TRH injection, measuring functional profile length (FPL), maximum urethral closure pressure (UCP), and closure pressures at the proximal quarter of the FPL (1/4 UCP) and at the distal quarter of the FPL (3/4 UCP). Significant reductions were found in both FPL (p = 0.022) and 3/4 UCP (p = 0.014) in the 'active' group as compared with the 'placebo' group. TRH administration significantly reduces the distal urethral closure pressure. Clarification of the mechanism of action of TRH on the urethra may point the way towards new developments in the management of female voiding dysfunction.

Structural requirements for stimulation by thyrotropin-releasing hormone of α-MSH release from rainbow trout (Oncorhynchus mykiss) pituitary fragments in vitro

Juvenile rainbow trout (Oncorhynchus mykiss) pituitary glands were isolated and the neurointermediate lobes (NILs) were removed from the partes distalis. NILs were surgically fragmented, pooled, and superfused in vitro with culture media, then treated with 3-min pulses of native thyrotropin-releasing hormone (TRH) or TRH analog; 10-min fractions were collected and stored (−20 °C) for subsequent analysis of α-melanocyte-stimulating hormone (α-MSH) content by specific radioimmunoassay. After 1–2 h of superfusion, α-MSH release from the NIL remained relatively constant; α-MSH-like immunoreactivity was not detected in eluate from the partes distalis in a series of parallel experiments. Native TRH stimulated acute releases of α-MSH from the NILs with a minimum effective dose of 10−9 M and an estimated ED50 of 1.73 × 10−9 M on the basis of increasing dose–response experiments; decreasing dose–response data provide an estimated minimum effective dose and ED50 of 10−9 and 1.57 × 10−9 M, respectively. No up- or down-regulatory effect was observed when NIL fragments were treated with repeated large (10−6 M) doses of TRH. By comparison, increasing pulse concentrations of pGlu-3-Me-His-Pro-NH2 (MeTRH) stimulated α-MSH release with a minimum effective dose of 10−10 M and an estimated ED50 of 1.56 × 10−9 M. Substitution of the histidine residue with phenylalanine decreased the stimulatory actions of TRH so that the minimum effective dose was 10−6 M. Substitution at either the amino terminus ([Glu1]TRH and [1-Me-(S)-dihydroorotyl1]TRH) or carboxy terminus (pGlu-His and TRH-Gly) resulted in near complete loss of bioactivity. To the best of our knowledge, this is the first investigation of the structural requirements for TRH biological activity in the teleost pituitary. Our data indicate that the structural criteria for TRH stimulation of α-MSH from the teleost pituitary are highly conservative; modification of TRH beyond the methylation of the histidine residue results in massive loss of biological activity. These data are consistent with our previous demonstrations of highly conservative structural requirements for TRH-receptor recognition in the trout pituitary and hypothalamus.

Effects of TA-0910, an orally active TRH analog, on the spinal reflex in spinal rats

Effects of TA-0910 (1-methyl-(S)-4,5-dihydroorotyl-L-histidyl-L-prolinamide), a new thyrotropin releasing hormone (TRH) analog, on spinal reflex potentials and flexor reflexes were compared with those of TRH in C1-spinal rats. Intravenously administered TA-0910 and TRH produced dose-dependent increases in the amplitudes of mono- and polysynaptic reflex potentials and withdrawal flexor reflexes. TA-0910 was more potent and more long-lasting than TRH. The stimulating actions of TA-0910 and TRH on the monosynaptic reflex potential were not antagonized by pretreatment with atropine, cyproheptadine, haloperidol or prazosin, suggesting no involvement of the cholinergic, serotonergic, dopaminergic or noradrenergic system. Intraduodenally administered TA-0910 also produced a lasting potentiation of the withdrawal flexor reflex, but intraduodenally administered TRH showed no effect. These results suggest that TA-0910 may be a more useful drug than TRH for spinal functional disorders.

Thyrotropin-releasing hormone enhances excitatory postsynaptic potentials in neocortical neurons of the rat in vitro

Several lines of evidence suggest a modulatory effect of thyrotropin-releasing hormone (TRH) on synaptic transmission in the mammalian neocortex. In the present study, the effects of this tripeptide on intracellularly recorded neocortical pyramidal neurons were investigated using rat in vitro brain slice preparations. TRH (5 μM and 50 μM) added to the perfusion medium concentration-dependently increased the excitability of pyramidal neurons, reflected by the number of spikes evoked by a depolarizing current pulse and by the augmentation of the time integral of glutamatergic excitatory postsynaptic potentials (EPSPs). TRH increased preferentially the time integrals of the late components of EPSPs (1-EPSPs) and increased their voltage-dependence. The early components of the EPSPs (e-EPSPs) were changed to much lesser extent. Iontophoretically applied d-2-amino-5-phosphonovalerate ( d-APV) antagonized the TRH-induced increase of the 1-EPSPs. TRH also markedly enhanced the depolarizing responses evoked by iontophoretically applied N- methyl- d-aspartate (NMDA), while the depolarizing responses evoked by ( R, S)- α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and l-glutamate were not significantly affected. The depolarizing inward rectification present in all neurons studied was augmented by the higher concentration of TRH. The effects of TRH were incited after about 5 min and were long-lasting. In most neurons the effects of TRH on neuronal excitability did not completely recover during the 45 min washout period. The present data suggest that some of the non-hormonal actions of TRH in the neocortex may be due to an enhancement of glutamatergic synaptic transmission. The preferential enhancement of the NMDA receptor-mediated effects suggests a postsynaptic site of action of TRH.

Dopamine Inhibits TRH-Induced MAP Kinase Activation in Dispersed Rat Anterior Pituitary Cells

We recently reported the existence of two separate pathways for thyrotropin-releasing hormone (TRH)-induced mitogen-activated protein (MAP) kinase activation in GH3 pituitary tumor cells. To test the role of MAP kinase in TRH action, we examined the effect of dopamine (DA) on TRH-induced MAP kinase in primary cultures of rat anterior pituitary cells. 1 μM of DA attenuated 1 μM TRH-induced MAP kinase activity and phosphorylation. 100 ng/ml of islet-activating protein (IAP) blocked these inhibitory effects of DA. These results suggest that crosstalk exists between the DA signaling pathway and the TRH-stimulated MAP kinase activating pathway in rat anterior pituitary cells.

Microinjection of thyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus stimulates gastric contractility

Changes in gastric contractility following microinjection of thyrotropin-releasing hormone (TRH) into the paraventricular nucleus of the hypothalamus (PVN) were examined in fasted, urethane-anesthetized rats. Gastric contractility was measured with extraluminal force transducers and analysed by computer. Unilateral and bilateral PVN microinjections of TRH (0.5 and 1.0 μg) significantly increased the force index of gastric contractions from 0 to 60 min postinjection, when compared with animals microinjected with 0.1 μg TRH, 0.1% BSA or TRH (0.5 and 1.0 μg TRH) in sites adjacent to the PVN. The gastric force index was also significantly elevated from 61 to 120 min postinjection in rats receiving bilateral PVN microinjections of TRH (0.5 and 1.0 μg). Peak gastric responses occurred within 10–20 min postinjection and represented an approximately eight-fold increase over basal values. In the remaining groups, the force index was not significantly altered from preinjection values. The excitatory action of TRH (1.0 μg) on gastric contractility was completely abolished by subdiaphragmatic vagotomy. These results suggest that TRH acts within the PVN to stimulate gastric contractility via vagal-dependent pathways.

A Possible Involvement of Tyrosine Kinase in TRH-Induced Prolactin Secretion in GH3 Cells

Thyrotropin-releasing hormone (TRH) is a well-known regulatory factor of prolactin (PRL) secretion and synthesis in lactotrophs. Recently we have found that TRH stimulates early tyrosine phosphorylation of MAP kinase in GH3 cells. Then we investigated whether tyrosine phosphorylation in TRH action is involved in TRH-stimulated PRL secretion by GH3 cells, using a 4-hydroxycinnamamide derivative (ST638), a tyrosine kinase inhibitor. TRH-stimulated tyrosine phosphorylation of MAP kinase and PRL secretion were remarkably inhibited by ST638 treatment. These results suggest that tyrosine phosphorylation of MAP kinase is strongly associated with TRH-stimulated PRL secretion.

Cerebrospinal fluid TRH immunoreactivity in anorexia nervosa

Central nervous system (CNS) thyrotropin-releasing hormone (TRH) activity is of interest in patients with anorexia nervosa. First, anorexics have peripheral thyroid abnormalities that appear to be related to weight and nutritional status. Second, CNS TRH activity may effect many other physiologic systems that are known to be disturbed in patients with anorexia nervosa. We found that anorexic patients, when both underweight and studied after attaining goal weight, had significantly reduced CSF TRH concentrations in comparison to controls. These data suggest that weight gain or increased caloric intake, in contrast to its large effect on peripheral thyroid function, has relatively little effect on CNS TRH activity. The reason for reduced CSF TRH in goal weight anorexics is not known but could be trait related, a persistent defect slow to normalize after weight gain, or related to these patients still being at a weight lower than controls. Finally, in terms of CSF TRH concentrations, this study suggests that anorexia nervosa has a different pathophysiology than major depressive disorder.

Intracisternal thyrotropin‐releasing hormone‐induced vagally mediated gastric protection against ethanol lesions: Central and peripheral mechanisms

The vagus is involved in mediating gastric cytoprotection and adaptive cytoprotection. However, the central and peripheral mechanisms through which the vagus expresses its action are still poorly known. Medullary thyrotropin-releasing hormone (TRH) plays an important role in the vagal regulation of gastric function. The stable TRH analogue, RX 77368, micro-injected into the cisterna magna or the dorsal motor nucleus (DMN) of the vagus at a dose that did not influence gastric acid secretion prevented gastric injury induced by intragastric administration of 60% ethanol in conscious or urethane-anaesthetized rats. The cytoprotective action of TRH is mediated through vagal cholinergic release of prostaglandin E2 (PGE2). Prostaglandin E2 action is unrelated to changes in gastric mucosal blood flow (GMBF). In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin sensitive afferent fibres and nitric oxide, both of which mediate the associated increase in GMBF induced by intracisternal injection of RX 77368. These data indicate that medullary TRH induces vagally mediated gastric protection against ethanol lesions. Its action is expressed through the muscarinic dependent release of PGE2 and nitric oxide, and efferent function of capsaicin-sensitive afferent fibres releasing CGRP.

Role of laminin on prolactin and gonadotrophin release from anterior pituitaries of male rats

The effect of rat laminin on the release of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from anterior pituitaries of adult male rats was studied in vitro. Laminin had a bidirectional effect on basal release of PRL, being stimulatory at 10 −12M and inhibitory at 10 −9 and 10 −8M. LH release was only stimulated by the 10 −12M concentration and no changes in FSH release were observed. Laminin did not modify the stimulatory action of thyrotropin-releasing hormone (TRH) nor luteinizing hormone releasing hormone (LHRH), but the response of FSH to LHRH was inhibited with a maximal effect at 10 −10M. To assess its physiological role, the effect of a rabbit antibody to laminin on the release of PRL, LH and FSH was also studied. IgG anti-laminin on at 2 × 10 −7M had highly significant stimulatory effect on PRL release after 3 and 5 hr of incubation, as compared to IgG from normal rabbit serum and medium alone used as controls. No changes on the release of LH and FSH were detected. These results suggest that laminin plays a physiologically significant inhibitory role on PRL release at the pituitary level in vitro.

Effect of thyrotropin releasing hormone on U-50,488H-induced pharmacological responses in mice

The effect of thyrotropin releasing hormone (TRH) administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) on the analgesic and hypothermic actions of U-50,488H, a highly selective κ-opiate agonist, was determined in male Swiss Webster mice. Intraperitoneal administration of U-50,488H (8–32 mg/kg) produced a dose-dependent analgesia as assessed by the tail-flick test. Similarly, U-50,488H also produced a dose-dependent hypothermia in mice. TRH was administered s.c. 15 min or i.c.v. 5 min prior to U-50,488H injection. TRH (1,3 and 10 mg/kg, s.c.) dose-dependently attenuated the analgesic effect of U-50,488H (32 mg/kg), whereas TRH at these doses displayed almost complete blockade of the hypothermic effect of U-50,488H. Similarly, TRH (0.03, 0.3 and 1 μg/mouse; i.c.v.) dose-dependently attenuated the analgesic and hypothermic actions of U-50,488H, indicating the central component in the action of TRH. TRH alone in doses used showed no change in either basal tail-flick latency or body temperature, demonstrating the lack of effect of this drug alone on pain and temperature responsiveness. Studies haven shown that TRH does not modify morphine or β-endorphin-induced analgesia in animals nor does it effect the binding of μ-opiate agonist or antagonist to brain membranes. Previous studies from this laboratory have indicated that κ-opiates but not μ-opiates inhibit the binding of [ 3H][3-MeHis 2]-TRH to brain membranes. The present studies clearly show that TRH modulates the pharmacological actions mediated by κ-opiate agonists in mice. Thus, these studies provide further in vivo evidence for an acute interaction between TRH and κ-opiates.

A study of the barium-sensitive and -insensitive components of the action of thyrotropin-releasing hormone on lumbar motoneurons of the rat isolated spinal cord.

The electrophysiological action of thyrotropin-releasing hormone (TRH) on rat spinal motoneurons was studied in vitro using single-electrode voltage- and current-clamp techniques. In current-clamp conditions TRH elicited a slowly developing depolarization, associated with a large input resistance increase and sustained neuronal firing; the primary metabolites of TRH were ineffective. Under voltage-clamp conditions in the presence of tetrodotoxin, TRH evoked a large inward current (ITRH; peaking at approximately -40 mV) associated with a large input conductance fall. Only 44% of cells displayed ITRH reversal; when the chord conductance values of these cells were plotted against membrane potential, a bell-shaped relation occurred, indicating voltage-dependent block by TRH of a persistent conductance active over a wide range of membrane potentials. ITRH reversal values were shifted to more positive levels in high K+ solution in Nernstian fashion; hence a large proportion of the TRH response is suggested to be mediated by the block of a K+ conductance (IK(T)). IK(T) (and its voltage-dependent block by TRH) was resistant to certain K+ channel antagonists (tetraethylammonium, Cs+, 4-aminopyridine or apamin), but was depressed by Ba2+. The Ba(2+)-resistant fraction of ITRH was attenuated by Cd2+, Mn2+ or Co2+, indicating that it probably involved a Ca(2+)-sensitive inward current. Concomitant application of Ba2+ and Cd2+ induced a near-total block of the response to TRH. It is suggested that suppression of IK(T), associated with the onset of a Ca(2+)-sensitive current, can explain the excitatory effect of TRH on rat spinal motoneurons.

Low‐Dose Thyrotropin‐Releasing Hormone Effects in Cognitively Impaired Alcoholics

The cognitive effects of a low dose of thyrotropin-releasing hormone (TRH) (2.0 mg, IV) were evaluated in 18 chronic alcoholic patients who exhibited memory dysfunction secondary to chronic alcohol abuse. The study used a double-blind crossover design that compared cognitive functions in patients with 2.0 mg of TRH IV as compared with a placebo. TRH was chosen because of its ability to enhance cholinergic transmission. Only minimal effects were seen with TRH. Patients with a shorter duration of alcohol use (mean of 16 years) performed significantly better with TRH as compared with placebo on a test involving verbal learning and memory. Those with a more chronic history of alcohol abuse (mean of 27 years) did not show such a response. All of the subjects showed cardiovascular response to TRH. Factors that may have contributed to the results of our study are discussed. It is our impression that future studies evaluating the cognitive effects of TRH in chronic alcoholics need to include an evaluation of the functional activity of TRH in the brain.

Sympathectomy and beta-adrenergic blockade during lung maturation stimulated by TRH and cortisol in fetal sheep

To test whether beta-adrenergic mechanisms and the sympathetic nervous system are involved in the synergistic action of thyrotropin-releasing hormone (TRH) and cortisol on lung maturation, fetal sheep (n = 32) were infused from 121 to 128 days of gestation with saline, TRH + cortisol, TRH + cortisol + beta-adrenergic blocker, or TRH + cortisol after chemical sympathectomy with 6-hydroxydopamine. TRH + cortisol increased lung distensibility and stability and alveolar concentrations of saturated phosphatidylcholine two- to threefold over control fetuses. beta-Adrenergic blockade prevented the increase in distensibility in response to TRH + cortisol. Sympathectomy did not impair the increase in distensibility and stability in response to TRH + cortisol but inhibited the increase in alveolar total phospholipids. Tissue concentrations of saturated phosphatidylcholine increased in TRH + cortisol-treated fetuses after either sympathectomy or beta-adrenergic blockade. We concluded that during lung maturation by TRH + cortisol 1) sympathetic mechanisms are requisite for surfactant release, 2) nonneurogenic beta-adrenergic mechanisms are requisite for the maturation of the mechanical properties of the lung and 3) stimulation of surfactant synthesis is independent of beta-adrenergic action and the sympathetic nervous system.

Regulation of canine gallbladder motility by brain peptides

Background: Brain peptides alter most gastrointestinal functions, but their effects on gallbladder motility have not been examined in detail. Methods: Studies were conducted in awake, male beagle dogs. Results: Of 30 brain peptides evaluated, thyrotropin-releasing hormone (TRH) and calcitonin gene-related peptide (CGRP) inhibited CCK- and meal-induced gallbladder contraction. These responses were abolished by ganglionic blockade. Truncal vagotomy prevented the central inhibitory action of TRH but not that of CGRP, whereas noradrenergic blockade prevented the central inhibitory action of CGRP but not that of TRH. Muscarinic blockade did not prevent the relaxing effect of cerebral TRH but pretreatment with the vasoactive intestinal peptide (VIP) antagonist, (4Cl-d-Phe6-Leu17)VIP, significantly attenuated gallbladder relaxation induced by cerebral TRH: the combination of both VIP and muscarinic antagonists abolished TRH-induced gallbladder relaxation. α-Adrenergic receptor blockade but neither β-adrenergic blockade nor adrenalectomy abolished gallbladder relaxation induced by cerebral CGRP. Intravenous infusion of VIP and norepinephrine inhibited CCK-induced gallbladder contraction and these responses were abolished dose dependently by intravenous infusion of (4Cl-d-Phe6-Leu17)VIP and phentolamine, respectively. Conclusions: Cerebral TRH inhibits canine gallbladder contraction by stimulation of vagal outflow and subsequent release of VIP acting via its specific receptor whereas cerebral CGRP inhibits gallbladder contraction by stimulation of sympathetic, noradrenergic outflow via α-adrenergic receptors.

Influence of thyrotropin-releasing hormone and catecholaminergic interactions on CNS ethanol sensitivity.

The role of catecholamine neuronal systems in mediating the analeptic and thermogenic effects of thyrotropin-releasing hormone (TRH) was examined in long-sleep (LS) and short-sleep (SS) mice. TRH [0.1 to 40 micrograms, intracerebroventricularly (icv)] was associated with a reduction in the sleep times of LS mice, but no dose of TRH had any effect on sleep times of SS mice. However, TRH (20 micrograms, icv) produced a 1.0 degree to 1.5 degrees C attenuation of the ethanol-induced hypothermia in both LS and SS mice. TRH did not change the rate of ethanol elimination in either line of mice, suggesting that the reduction in LS sleep times and attenuation of LS and SS hypothermia were due to decreased CNS ethanol sensitivity rather than an increase in the rate of ethanol metabolism. TRH (20 micrograms, icv) given alone produced an activation of central and peripheral catecholamine systems in LS, but not SS mice, as reflected by an increase in the in vivo tyrosine hydroxylase (TH) activity in the brain and adrenal gland. TRH, given with ethanol, prevented or attenuated ethanol-induced decreases in the brain and adrenal gland in vivo TH activity in LS mice but not SS mice. Thus, there was an association between the ability of TRH to produce an activation of catecholamine neuronal systems (increased rate of catecholamine biosynthesis) and the analeptic action of TRH to reduce the CNS depressant effects of ethanol (decreased sleep times).(ABSTRACT TRUNCATED AT 250 WORDS)