RESUMO
BACKGROUND AND PURPOSE: Ghrelin, a gut-brain peptide, is considered a gastroprotective factor in gastric mucosa. We investigated the role of prostaglandins (PG) and the possible interplay between PGs and nitric oxide (NO) in ghrelin gastroprotection against ethanol (EtOH)-induced gastric lesions. EXPERIMENTAL APPROACH: We examined the effects of (1) central ghrelin (4 mug per rat) injection on PGE(2) accumulation in normal or EtOH-lesioned gastric mucosa, (2) pretreatment with indomethacin (10 mg kg(-1), p.o.), a non-selective cyclooxygenase (COX) inhibitor, and with a selective COX-1, SC560 (5 mg kg(-1), p.o.) or COX-2 inhibitor, celecoxib (3.5 mg kg(-1), p.o.) on ghrelin gastroprotection against 50% EtOH (1 mL per rat)-induced gastric lesions, (3) the NO synthase inhibitor, L-NAME (70 mg kg(-1), s.c), on gastric PGE(2) content in ghrelin-treated rats and (4) central ghrelin on the expression of constitutive and inducible NOS and COX mRNA and on the localization of the immunoreactivity for COX-2 in the gastric mucosa exposed to EtOH. KEY RESULTS: Ghrelin increased PGE(2) in normal mucosa, whereas, it reversed the EtOH-induced PGE(2) surge. Ghrelin had no effect on mucosal COX-1 expression but reduced the EtOH-induced increase in COX-2 expression and immunoreactivity. Indomethacin and SC560, but not celecoxib, removed ghrelin gastroprotection. L-NAME prevented the PGE(2) surge induced by ghrelin and, like indomethacin, reduced EtOH-induced PGE(2) increase. Ghrelin enhanced eNOS expression and reduced iNOS mRNA. CONCLUSIONS AND IMPLICATIONS: This study shows that COX-1-derived PGs are mainly involved in ghrelin gastroprotection and that the constitutive-derived NO together with PGE(2) are involved in ghrelin gastroprotective activity.
Assuntos
Dinoprostona/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Grelina/farmacologia , Óxido Nítrico/metabolismo , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Etanol/toxicidade , Mucosa Gástrica/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológicoRESUMO
Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R) has been previously shown to inhibit gastric acid secretion in pylorus-ligated rats. Two isoforms of GHS-R have been identified: GHS-R(1a) and GHS-R(1b). The present study aimed: (i) to characterise the type of GHS-R involved in the central gastric inhibitory activity of ghrelin by using des-octanoyl ghrelin, and synthetic GHS-R(1a) agonist (EP1572) and antagonist (D-Lys(3)-GHRP-6) and (ii) to investigate the relationship between ghrelin and cortistatin (CST) in the control of gastric acid secretion by using the natural neuropeptide CST-14 and the synthetic octapeptide CST-8. The specific interactions of all the compounds with GHS-R(1a) were determined by comparing their ability to displace labelled ghrelin or somatostatin from its receptors on rat hypothalamic membranes or on rat cardiomyocyte, respectively. Intracerebroventricular administration of 0.01 and 1 nmol/rat des-octanoyl ghrelin did not affect gastric acid secretion in pylorus-ligated rats, whereas EP1572 either i.c.v. (0.01-1 nmol/rat) or i.p. (10 and 20 nmol/kg) inhibited acid gastric secretion. Preteatment with D-Lys(3)GHRP-6 (3 nmol/rat, i.c.v.) was able to remove the inhibitory action of ghrelin (0.01 nmol/rat, i.c.v.) on gastric acid volume and acid output, thus indicating that the type 1a GHS-R likely mediates the gastric inhibitory action of ghrelin. This is supported by binding data showing that D-Lys(3)GHRP-6, but not des-octanoyl ghrelin, binds to hypothalamic GHS-R. CST-14 (1 nmol/rat, i.c.v.) did not affect either basal or ghrelin inhibition of gastric acid secretion. CST-8 (1 nmol/rat, i.c.v.) was able to counteract the gastric ghrelin response. The observation that CST-14 binds both GHR-S and somatostatin receptors, whereas CST-8 specifically displaces only ghrelin binding, indicates that CST-8 behaves as a GHS-R(1a) antagonist.
Assuntos
Ácido Gástrico/metabolismo , Hormônios Peptídicos/fisiologia , Peptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Somatostatina/metabolismo , Análise de Variância , Animais , Ligação Competitiva , Cistatinas/metabolismo , Regulação para Baixo , Grelina , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Miócitos Cardíacos/metabolismo , Neuropeptídeos/metabolismo , Peptídeos Cíclicos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GrelinaRESUMO
This study was designed to evaluate whether or not continuous intracerebroventricular infusion of leptin (1.5 microg/rat/24 h, for 28 days) produced different regional response on the skeleton of growing rats. Leptin reduce the accretion of total femoral bone mineral content (BMC) and density (BMD). This effect was related to a reduction of metaphyseal femur as no changes were detected in the diaphysis. Despite the reduced accretion in the volumetric of both femur and tibia compared to controls, leptin had no significant effects on the lumbar vertebrae. Urine deoxypyrydinoline and serum osteocalcin remained more elevated in the leptin-treated group as compared to controls. The results demonstrate that long-term central infusion of leptin activates bone remodeling with a negative balance. Leptin induces distinct responses in the different structure of bone and in the axial and appendicular skeleton.
Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Encéfalo/metabolismo , Leptina/administração & dosagem , Animais , Peso Corporal , Osso e Ossos/metabolismo , Leptina/metabolismo , Masculino , Osteocalcina/sangue , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
We studied the effect of the acute central administration of obestatin on food intake and body weight in short-term starved male rats, and those of 28-day continuous intracerebroventricular (icv) infusion of obestatin in free feeding rats. In 16-h starved rats, obestatin induced a trend toward a reduction of food intake that did not reach statistical significance. In fed rats, the icv infusion of obestatin significantly decreased food consumption in the first day of treatment; but the anorexigenic effect of obestatin vanished thereafter. Interestingly, the body weight of rats infused for 28 days with obestatin was superimposable to that of the respective control at all time intervals. In all, our results indicate that the anorexigenic effect of obestatin is of little account and that the peptide does not modify energy metabolism in the long-term administration.
Assuntos
Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hormônios Peptídicos/farmacologia , Animais , Ventrículos Cerebrais , Infusões Parenterais , Injeções Intraventriculares , Masculino , Hormônios Peptídicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , InaniçãoRESUMO
Various compounds with different blocking potencies on histamine H2-receptors were administered to rats both into the carotid (ia) and into the brain ventricles (icv) and their effects on PRL release were evaluated. The drugs were cimetidine, as reference compound, ranitidine, 5 to 7 times as potent, and oxmetidine, 8 to 10 times as potent. PRL was measured in blood samples collected at -15, 0 and +5, +10, +20 and +40 min after treatment. Cimetidine (80 mg/kg) and ranitidine (30 mg/kg), when injected ia as a single bolus, induced prompt increases (P less than 0.01) in PRL. On the contrary, oxmetidine (the most potent H2 antagonist), even at the high dose of 80 mg/kg ia, had no effect on PRL release. When the drugs were given icv (0.2 mumol/rat or 0.8 mumol/rat), none of them caused any significant PRL release. These results suggest that histamine H2-blocking potency is not correlated with PRL release. Furthermore, the PRL-releasing activity of the drugs seems not to be due to any action on the central neural control of PRL secretion. This comparative study shows that it is possible (as with oxmetidine) to achieve complete dissociation of the H2-receptor blocking action from the unwanted PRL-release stimulating effect.
Assuntos
Prolactina/sangue , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos/metabolismo , Animais , Cimetidina/farmacologia , Furanos/farmacologia , Imidazóis/farmacologia , Masculino , Ranitidina , Ratos , Ratos EndogâmicosRESUMO
The effects of intracerebroventricular (icv;25ng/rat) or iv (10 micrograms/kg) salmon calcitonin (sCT) on PRL secretion were determined in lactating rats and compared to the effects in intact or ovariectomized-estrogen-treated female rats. The icv or iv injections of sCT 9 days after estrogen treatment did not significantly lower the PRL levels in intact rats. In ovariectomized-estrogen-primed animals, sCT (icv or iv) did not modify the afternoon surge of PRL secretion when injected during the surge, nor did it delay or attenuate the increasing secretory activity when administered (iv) before the afternoon surge had begun. On the contrary, 30 or 60 min after the icv or iv administration of sCT to lactating rats, suckling-induced PRL secretion was prevented. These results and our previous evidence that a greater dose of sCT is needed to decrease the less intense morphine- or stress-induced PRL secretion indicate differential hypoprolactinemic properties of sCT, which are particularly striking during lactation. While the mechanisms underlying these selective activities deserve further investigation, the proposed participation of PRL in the regulation of calcium metabolism during lactation suggests that the potent PRL inhibitory effect of CT in this condition should be regarded as one factor in the complex mechanism that prevents bone loss and protects the maternal skeleton.
Assuntos
Calcitonina/farmacologia , Lactação , Prolactina/metabolismo , Animais , Calcitonina/administração & dosagem , Castração , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Injeções Intravenosas , Injeções Intraventriculares , Gravidez , Prolactina/sangue , Ratos , Ratos EndogâmicosRESUMO
Ghrelin, the endogenous ligand for GH secretagogue receptors, has been reported to influence acid gastric secretion and motility, but its potential gastroprotective effect is unknown. The aims of this study were 1) to examine the effects of central and peripheral administration of ghrelin on ethanol-induced gastric ulcers in conscious rats, and 2) to investigate the possible roles of nitric oxide (NO), vagal nerve, and sensory fibers in the gastric effects of ghrelin. Ghrelin was administered either intracerebroventricularly or sc 30 min before ethanol, and mucosal lesions were examined macroscopically. Additionally, rats were either treated with the inhibitor of NO synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME) or underwent bilateral cervical vagotomy or capsaicin-induced sensory denervation. Conventional histology and immunohistochemistry for ghrelin, gastrin, and somatostatin were performed on gastric specimens from representative rats. Central ghrelin (4-4,000 ng/rat) dose-dependently reduced ethanol-induced gastric ulcers by 39-77%. Subcutaneous ghrelin administration (80 micro g/kg) reduced ulcer depth only. L-NAME and capsaicin, but not vagotomy, prevented the gastroprotective effect of central ghrelin (4000 ng/rat). This is the first evidence that ghrelin exerts a potent central gastroprotective activity against ethanol-induced lesions. The gastroprotective effect of ghrelin is mediated by endogenous NO release and requires the integrity of sensory nerve fibers.
Assuntos
Etanol , Hormônios Peptídicos/administração & dosagem , Úlcera Gástrica/prevenção & controle , Animais , Capsaicina/administração & dosagem , Denervação , Inibidores Enzimáticos/farmacologia , Mucosa Gástrica/química , Mucosa Gástrica/inervação , Mucosa Gástrica/patologia , Gastrinas/análise , Grelina , Imuno-Histoquímica , Injeções Intraventriculares , Injeções Subcutâneas , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Hormônios Peptídicos/análise , Ratos , Ratos Sprague-Dawley , Somatostatina/análise , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , VagotomiaRESUMO
Data have been collected indicating possible functions for histamine in brain but there are only a very few data, collected exclusively with behavioural tests, about the effects of histamine on the perception of the pain, an important aspect in the homeostasis of the human body. The purpose of the present study was to investigate the effects of histamine, injected directly into the lateral cerebral ventriculi on the firing of nociceptive thalamic neurones, detected by electrophysiological techniques in rats rendered arthritic by injection of Freund's adjuvant into the left hindfoot. The noxious test stimuli used were either extension or flexion of the ankle or mild lateral pressure on the heel. With increasing doses of histamine (5, 10, 20, 40 micrograms) it was possible to observe an increasing inhibitory and long-lasting effects of the evoked activity, with a significant dose-effect linear regression. The inhibitory responses, induced by histamine, probably by a hyperpolarization phenomenon that decreased excitatory postsynaptic potentials, were clues for the presence of a histaminergic pathway in parallel with and/or in connection with other adrenergic, gabaergic, serotoninergic and opioidoergic pathways that regulate the transmission and the modulation of algogenic electrophysiological messages.
Assuntos
Analgésicos/farmacologia , Histamina/farmacologia , Animais , Artrite Experimental/complicações , Encéfalo , Eletrofisiologia , Potenciais Evocados/efeitos dos fármacos , Histamina/administração & dosagem , Técnicas In Vitro , Injeções , Injeções Intraventriculares , Masculino , Dor/tratamento farmacológico , Dor/etiologia , Ratos , Ratos Sprague-Dawley , TálamoRESUMO
This study examined the possible peripheral activity of eel calcitonin in the modulation of the response to noxious pressure on inflamed paws in rats (Randall and Selitto test). The intraplantar injection of eel calcitonin (20-200 ng/rat) but not the subcutaneous administration (200 ng and 2 micrograms/rat, s.c.), was able to significantly inhibit hyperalgesia induced by intraplantar injection of carrageenin. The development of oedema on the other hand was not inhibited. The intraplantar administration of eel calcitonin (200 ng/rat) in a non-inflamed paw did not modify paw pressure thresholds. Eel calcitonin (200 ng/rat, intraplantar, i.pl.) was also able to elicit an antinociceptive effect on formalin-induced hyperalgesia, both when the peptide was injected before or after (60 min) formalin. This effect, at difference with morphine (80 micrograms/rat, i.pl.), was not blocked by naloxone (10 micrograms/rat, i.pl.). These results demonstrate the local antinociceptive effect of eel calcitonin in inflammatory pain and might indicate a new way of using calcitonin in the control of pain.
Assuntos
Analgésicos/farmacologia , Calcitonina/farmacologia , Inflamação/fisiopatologia , Analgésicos/administração & dosagem , Animais , Calcitonina/administração & dosagem , Carragenina , Edema/induzido quimicamente , Edema/patologia , Pé , Injeções , Masculino , Naloxona/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The effects of intracerebroventricular (i.c.v.) injection of histamine, the H1 agonist 2-methyl-histamine and the H2 agonist dimaprit were tested on carrageenin induced hyperalgesia by the Randall-Selitto paw pressure test in the rat. Treatment with histamine (0.1, 0.2, 0.4 mumol/rat, i.c.v.) 150 min after intraplantar carrageenin (0.1 ml of 1% solution) caused a significant increase of paw pressure thresholds in inflamed (but not in non-inflamed) paws. The magnitude and the duration of the antinociceptive effects of histamine were dose-dependent. Administration of 2-methyl-histamine (0.2, 0.4, 0.8, 1.0 mumol/rat, i.c.v.) and dimaprit (0.1, 0.2, 0.4, 0.8 mumol/rat, i.c.v.) also displayed dose-dependent blockade of carrageenin-induced hyperalgesia. Antinociceptive ED50 values calculated 30 min after drug treatments were: histamine 0.18 mumol/rat; 2-methyl-histamine 0.65 mumol/rat; dimaprit 0.33 mumol/rat. These data indicate that histamine through central H1 and H2 receptors exerts an inhibitory role in the control of nociception in pain resulting from inflammation.
Assuntos
Sistema Nervoso Central/fisiopatologia , Histamina/fisiologia , Hiperalgesia/fisiopatologia , Animais , Carragenina , Dimaprit/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Hiperalgesia/induzido quimicamente , Masculino , Metilistaminas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
1. The mechanisms involved in the protective effect of amylin (administered into the brain ventricle, i.c.v.) on gastric ulcers induced by the oral administration of ethanol 50% (EtOH, 2 ml/rat) or indomethacin (indomethacin, 20 mg kg(-1), at a dosing volume of 5 ml) were investigated in rats. 2. The possible involvement of endogenous nitric oxide (NO) in the beneficial effect of amylin against EtOH-induced ulcers was examined. The inhibitor of NO-synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 70 mg kg(-1), s.c.) was injected 30 min before amylin (2.2 microg/rat, i.c.v.) followed by EtOH after a further 30 min. Rats were sacrificed 1 h after EtOH. L-NAME completely removed the protective effect of amylin. 3. The interaction between amylin and gastric nonprotein sulfhydryl groups was studied. The rats were treated with N-ethyl-maleimide (NEM, 25 mg kg(-1), s.c.) 30 min before amylin (2.2 microg/rat, i.c.v.) followed by EtOH 30 min after or by indomethacin 5 min after amylin. Rats were sacrificed 1 h or 6 h respectively after EtOH or indomethacin. NEM counteracted the protective effect of amylin against EtOH-induced ulcers but not against those provoked by indomethacin. 4. To determine whether amylin was able to promote ulcer healing, the peptide was injected 5 min after EtOH or 1 h after indomethacin. In the case of EtOH, the beneficial effect of amylin was lost whereas it was still effective on indomethacin-induced ulcers. 5. The results indicate that: the mechanisms involved in the antiulcer effects of amylin are different in these two types of gastric lesions probably because of the different etiopathology of various types of ulcers. Endogenous NO and nonprotein sulfhydryl groups are involved in the mucosal protective effects of amylin on EtOH and not on indomethacin-induced ulcers. Furthermore the effectiveness of amylin against indomethacin-induced lesions when administered after the ulcerogenic process has started suggests that amylin is involved not only in the protection but also in the healing mechanisms in this type of ulcer.
Assuntos
Amiloide/uso terapêutico , Antiulcerosos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Úlcera Gástrica/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Calcitonina/administração & dosagem , Calcitonina/farmacologia , Inibidores Enzimáticos/farmacologia , Etanol , Indometacina/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Fatores de TempoRESUMO
1. The effect of amylin on gastric ulcers induced by oral administration of indomethacin (Indo, 20 mg kg-1 at a dosing volume of 5 ml) or ethanol 50% (EtOH, 1 ml/rat) was investigated in conscious rats. 2. Amylin given intracerebroventricularly (0.22, 0.66 and 2.2 micrograms/rat, i.c.v.) demonstrated a dose-dependent cytoprotective effect against both Indo and EtOH-induced ulcers. In contrast, amylin, given subcutaneously at doses effective in inhibiting acid gastric secretion (2.5, 10 and 40 micrograms kg-1, s.c.), did not show any cytoprotective effect. 3. The interaction between amylin and endogenous nitric oxide (NO) in the maintenance of gastric mucosal integrity was investigated by pretreating the rats with a selective inhibitor of NO-synthesis, NG-nitro-L-arginine methyl ester (L-NAME, 25 and 70 mg kg-1, s.c.). Administration of L-NAME to rats did not significantly increase the degree of the Indo-induced ulcer index and was not able to remove the protective effect of amylin on Indo-induced ulcers, thus excluding a role for endogenous NO in mediating the protective effect of this peptide. 4. To determine whether the cytoprotective effect of amylin was mediated by endogenous prostaglandins, we studied the effect of amylin (2.2 micrograms/rat, i.c.v.) on EtOH- induced ulcers in rats pretreated with Indo (10 mg kg-1, s.c.) to inhibit prostanoid biosynthesis; Indo was injected 30 min before amylin and EtOH after a further 30 min. Pretreatment with Indo did not significantly increase the ulcer index induced by EtOH but counteracted the ability of amylin to prevent the ulcer formation. 5. These findings suggest that amylin exerts a gastroprotective activity that is not strictly related to inhibition of acid gastric secretion and can be partly explained through a prostaglandin-dependent mechanism mediated by receptors for the peptide in the brain. Amylin might be considered as a new brain-gut peptide.
Assuntos
Amiloide/administração & dosagem , Mucosa Gástrica/efeitos dos fármacos , Úlcera Gástrica/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Etanol , Determinação da Acidez Gástrica , Mucosa Gástrica/metabolismo , Indometacina , Injeções Intraventriculares , Injeções Subcutâneas , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamenteRESUMO
This study was undertaken to assess the sensitivity of hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), galactosylhydroxylysine (GHyl) and glucosylgalactosylhydroxylysine (GGHyl) to monitor bone response to estrogen deficiency and replacement by comparing their excretory patterns in ovariectomized aged (11-14 months old) rats. The ovariectomized (OVX) rats were randomized into two groups: (1) OVX plus vehicle; (2) OVX plus 17 beta-estradiol (17-beta E, 10 micrograms/kg, s.c., 4 days/week). Treatment with 17-beta E started immediately after OVX and continued for 60 days. The collagen catabolites were measured in urine for 1 month before OVX and thereafter for 60 days. In temporal coincidence with urine collection, bone area and bone mineral density (BMD) of lumbar vertebrae, femoral diaphysis and distal metaphysis were measured by dual-energy X-ray absorptiometry. In the untreated rats, BMD of the femoral metaphysis and lumbar vertebrae decreased significantly and the urinary excretion of LP, HP, GHyl and GGHyl increased with different patterns. In the treated rats, 17-beta E replacement prevented the increment in LP excretion, partially prevented the increase in HP excretion, but had no effect on the excretion of GHyl and GGHyl. In conclusion pyridinolines and glycosides have different sensitivities to the bone response to OVX. Glycoside excretion after OVX also reflects metabolic processes not strictly related to bone loss and, in contrast with LP, is not sensitive to estrogen replacement.
Assuntos
Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Hidroxilisina/análogos & derivados , Ovariectomia , Compostos de Piridínio/urina , Absorciometria de Fóton , Aminoácidos/urina , Animais , Biomarcadores/urina , Osso e Ossos/metabolismo , Feminino , Hidroxilisina/urina , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
The effects of neonatal passive immunization against GHRH on bone was examined in male and female rats. Pups were treated subcutaneously with GHRH-antiserum (GHRH-Ab) from day 1 to day 10 of age. Bone mineral content (BMC) and bone mineral density (BMD) were evaluated at monthly intervals until 7 months. Markers of bone resorption (urinary lysylpyridinoline, LP), bone formation (serum osteocalcin, OC) and serum IGF-I were measured at 2, 3 and 7 months. In male rats, GHRH-Ab did not modify BMC and BMD when compared with controls. In contrast, female rats demonstrated lower whole body and femoral BMC and BMD from 2 to 7 months of age. Reduced bone growth in the females was associated with lower IGF-I levels than controls at 2 and 3 months of age, whereas in males IGF-I titers did not change during the period of the study. LP excretion was higher in GHRH-Ab-treated rats at 2 and 3 months in both sexes. In females, no difference in OC values was recorded, whereas in GHRH-Ab-treated males, there was an increase in OC levels at 2 and 3 months. These data indicate that transient GHRH deprivation induces an osteopenic effect in female rats which is not evident in male rats.
Assuntos
Osso e Ossos/fisiologia , Hormônio Liberador de Hormônio do Crescimento/fisiologia , Sexo , Aminoácidos/urina , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Biomarcadores/urina , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Hormônio Liberador de Hormônio do Crescimento/imunologia , Soros Imunes/farmacologia , Imunização Passiva , Fator de Crescimento Insulin-Like I/análise , Masculino , Minerais/metabolismo , Osteocalcina/sangue , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacosRESUMO
To study possible age-related differences in the role of neuronal histaminergic pathways in the control of GH secretion, the effects of alpha-fluoromethylhistidine (alpha-FMH), an irreversible inhibitor of histamine (HA) synthesis, were examined on basal and opioid-induced GH release in neonatal and adult rats. The mechanisms involved in such effects were evaluated by measuring pituitary GH mRNA levels and hypothalamic levels of GH-releasing hormone (GHRH) and somatostatin (SRIF) mRNAs. Daily injection of alpha-FMH (20 mg/kg, s.c.) in pups of either sex, from birth until 10 days of age, caused a significant increase in baseline plasma GH and potentiated the GH response to the [Met5]-enkephalin analog FK 33-824 (1 mg/kg, s.c.) administered 3 h after the last alpha-FMH injection. GH and SRIF mRNA levels were significantly higher in alpha-FMH-treated pups than in controls, whereas no difference was observed in GHRH mRNA levels. In young adult male rats, acute administration of alpha-FMH (100 mg/kg, s.c., 3 h before) did not change significantly basal GH levels but potentiated FK 33-824 (0.3 mg/kg, intracarotid)-induced stimulation of GH secretion. Repeated administration of alpha-FMH (200 micrograms/rat, i.c.v., for 3 days) failed to modify basal and FK 33-824-induced GH secretion, caused a significant reduction in hypothalamic GHRH mRNA levels and left SRIF and GH mRNAs unchanged. These findings indicate that HA exerts an inhibitory effect on GH secretion in both neonatal and adult rats. The different effects of short-term HA depletion on hypothalamic and pituitary indices of somatotropic function observed at the two age periods may be ascribed to the immaturity of the HA system in early postnatal life and to a different functional role of GH-regulatory factors during ontogeny.
Assuntos
Envelhecimento/fisiologia , Hormônio do Crescimento/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Hipotálamo/metabolismo , Metilistidinas/farmacologia , Análise de Variância , Animais , Animais Recém-Nascidos , D-Ala(2),MePhe(4),Met(0)-ol-encefalina/farmacologia , Feminino , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/genética , Hipotálamo/efeitos dos fármacos , Masculino , Hipófise/química , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Somatostatina/genética , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: The aim of this study was to assess the responsiveness of two classes of bone resorption markers to the enhancement of osteoclastic activity induced by orchiectomy and to its inhibition by clodronate treatment in mature rats. DESIGN: Bone mineral density (BMD) at femural metaphysis, femural diaphysis, lumbar vertebrae, and the urinary excretion of pyridinoline (Pyr), deoxypyridinoline (D-Pyr), galactosylhydroxylysine (GHyl) and glucosylgalactosylhydroxylysine (GGHyl) were monitored at regular intervals for 30 days prior to and for 60 days following orchiectomy in eleven rats, divided into two groups: five rats untreated and the other six treated with clodronate. RESULTS: Prior to orchiectomy, a significant (P < 0.01) decrease in BMD was observed only at the distal femural metaphysis. This decrease appeared to be associated with a time-dependent increase in the urinary excretion of all markers. Following orchiectomy, the BMD of the untreated group decreased significantly (P < 0.01) at all bone sites. The bone loss was accompanied by a significant (P < 0.01) increase in Pyr and D-Pyr concentrations in urine, whereas urinary GHyl and GGHyl did not change significantly. In the clodronate-treated group, the BMD of the three skeletal sites did not change significantly, while the urinary excretion of all urinary biochemical markers decreased significantly (P < 0.001). CONCLUSION: This study showed that pyridinolines are able to monitor the bone response to orchiectomy and to clodronate treatment response in androgen-deficient mature male rat. whereas glycosides appear prone to confounding factors.
Assuntos
Envelhecimento/urina , Reabsorção Óssea/urina , Ácido Clodrônico/farmacologia , Orquiectomia , Animais , Biomarcadores/urina , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The present study was performed to evaluate the potential influence of the estrogen milieu in modulating the effects of GH/IGF stimulation by a GH-releasing peptide, hexarelin (HEXA), on bone metabolism and mineral density in middle-aged female rats. METHODS: HEXA was administered for 60 days (50 microg/kg s.c. twice a day) to intact and ovariectomized (OVX) 11-month-old female rats and changes in bone parameters were evaluated with respect to those of the same rats under baseline conditions and with those of control rats (intact and OVX) administered isovolumetric amounts of physiological saline. Serum total alkaline phosphatase (ALP) and urinary deoxypyridinoline (Dpd) were measured before and at various times during HEXA treatment. Bone mineral content (BMC) and density of lumbar vertebrae and femoral mid-diaphyses were measured by dual energy X-ray absorptiometry before and after treatment. In all groups, serum IGF-I levels were determined before and during treatment and the GH secretory response to HEXA was assessed at the end of the experiment. RESULTS: In intact rats, HEXA did not modify Dpd urinary excretion, induced a trend toward an increase of serum ALP activity and significantly increased BMC (+6.5%) and bone area (+4.1%) only at lumbar vertebrae. In OVX rats, HEXA did not modify the OVX-induced increase in bone turnover markers (Dpd and ALP) and did not affect the OVX-induced vertebral bone loss, but significantly increased BMC (+7.2%) and bone area (+5.3%) at femoral mid-diaphyses. HEXA significantly increased serum IGF-I levels at day 14, but not at day 60, in both intact and OVX rats, whereas the GH secretory response to HEXA was higher in the former than in the latter. CONCLUSIONS: Overall, the present data demonstrate that chronic HEXA treatment increases BMC and bone area at lumbar vertebrae in intact rats and at femoral diaphyses in OVX rats. The different sensitivity to HEXA of the skeletal districts examined is related to the estrogen milieu and may reflect a complex interplay between estrogens and GH/IGF function.
Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Estrogênios/metabolismo , Hormônios/farmacologia , Oligopeptídeos/farmacologia , Animais , Osso e Ossos/efeitos dos fármacos , Feminino , Hormônios/metabolismo , Oligopeptídeos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Intracerebroventricular injections of gamma-aminobutyric acid (GABA) and of the GABA-transaminase inhibitor, ethanolamine-O-sulphate (EOS), decreased the food intake of freely-fed (GABA and EOS) and food-deprived rats (EOS). The effect, still evident 24 h after treatment, was not decreased by the GABA receptor-blocker bicuculline. In contrast, intracerebroventricular injections of the GABA receptor-agonist, muscimol, caused an increase in food intake of freely-fed rats that was antagonized by bicuculline. The eating of animals receiving only bicuculline was stimulated in free-feeding and depressed in food-deprived conditions. These opposite results suggest that muscimol binds preferentially to some GABA receptors, probably those within the satiety-controlling areas (i.e. ventromedial hypothalamus), and that bicuculline influences mainly those postsynaptic neurons where GABAergic inputs prevail. These observations and the data from EOS- and GABA-treated rats provide evidence for involvement of GABA neurons in the regulation of feeding behaviour. The balance of the different effects produced in each of these areas by this modulation appears to be a decrease in feeding behaviour.
Assuntos
Encéfalo/fisiologia , Comportamento Alimentar/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/farmacologia , Etanolaminas/farmacologia , Feminino , Privação de Alimentos/fisiologia , Muscimol/farmacologia , RatosRESUMO
In order to investigate the effects of ageing on the cerebral receptors for calcitonin (CT), we used an in vitro autoradiographic method to study the distribution of the binding sites for eel CT (eCT) in young and old rat brain. The inhibitory action of eCT on adenylyl-cyclase (AC) activity upon isolated brain cell membranes was also evaluated. The results show area-specific reduction of binding particularly in the hypothalamus and pons medulla of the old rat. The inhibitory action of eCT on AC activity was significantly reduced in the same areas, whereas in the striatum and mesencephalon no changes were observed. The parallel decrease of binding of eCT and of the inhibitory action of eCT on AC in ageing may represent a functional decline of neuronal activities during ageing.
Assuntos
Adenilil Ciclases/metabolismo , Envelhecimento/metabolismo , Encéfalo/metabolismo , Calcitonina/metabolismo , Receptores de Superfície Celular/metabolismo , 1-Metil-3-Isobutilxantina/farmacologia , Animais , Autorradiografia , Encéfalo/crescimento & desenvolvimento , Calcitonina/farmacologia , Radioisótopos de Carbono , AMP Cíclico/metabolismo , Radioisótopos do Iodo , Cinética , Masculino , Especificidade de Órgãos , Ratos , Ratos Wistar , Receptores da Calcitonina , TrítioRESUMO
The effect of rat amylin on acid gastric secretion in the pylorus-ligated, unanesthetized rat system (Shay test) was examined. Amylin administered peripherally (2.5, 5, 10, 40, 100, or 160 micrograms/kg, SC) or intracerebroventricularly (1.5, 2.7, or 5 micrograms/rat, ICV) decreased acid gastric secretion in a dose-dependent manner. Central administration of amylin gave a stronger suppression of gastric secretion than peripheral injection. In addition, ICV-injected amylin inhibited insulin-stimulated acid gastric secretion and was effective in suppressing acid gastric secretion in rats depleted of somatostatin by pretreatment with cysteamine. This study suggests that amylin may participate in the central regulation of acid gastric secretion and indicates a possible biological function of amylin as a gastrointestinal peptide.