Effect Of Baclofen On Liquid And Solid Gastric Emptying In Rats.

Gamma-aminobutyric acid (GABA) is a potent inhibitory neurotransmitter. There is evidence that GABA(B) receptors located in the dorsal complex and in afferent fibers of the vagus nerve participate in the control of gastrointestinal motility. To assess the intracerebroventricularly (ICV) and intravenously (IV) effect of baclofen, a GABA(B) receptor agonist, on liquid and solid gastric emptying in rats. Adult male Wistar rats weighing 250-300 g (n = 6-8 animals) were used. Gastric emptying of liquid test meals labeled with phenol red was evaluated by the determination of percent gastric retention (%GR) 10 and 15 min after orogastric administration of saline and 10% glucose meals, respectively. Baclofen was injected ICV (1 and 2 µg/animal) through a tube implanted into the lateral ventricle of the brain and was injected IV (1 and 2 mg/kg) into a tail vein. The gastric emptying of liquid was determined 10 or 30 min after ICV and IV baclofen administration, respectively. The gastric emptying of the solid meal was assessed by the determination of percent gastric retention 2 h after the beginning of the ingestion of the habitual ratio by the animal, consumed over a period of 30 min. Baclofen was administered ICV (1 and 2 µg/animal) or IV (1 and 2 mg/kg) immediately after the end of the ingestion of the solid meal. The control groups received vehicle (sterile saline solution) ICV or IV. The group of animals receiving baclofen ICV (2 mg/animal) presented a significantly lower (P<0.05, Tukey test) %GR (mean ± SEM) of the saline (18.1 ± 2.5%) compared to control (33.2 ± 2.2%). In the group receiving the drug IV, the gastric retention of the same test meal did not differ from control. ICV and IV administration of baclofen had no effect on the gastric emptying of the 10% glucose solution compared to control. ICV administration of 1 or 2 mg baclofen/animal significantly increased the gastric retention of the solid test meal (57.9 ± 6.5% and 66.6 ± 6.3%, respectively) compared to control (35.1 ± 4.4%). The same phenomenon was observed only with the IV dose of 2 mg/kg (71.9 ± 2.6%) compared to control (52.7 ± 2.8%). Baclofen administered: 1. ICV (2 µg/animal), but not IV, increased gastric emptying of a non-caloric isotonic liquid test meal (saline); 2. when administered ICV or IV, it had no effect of gastric emptying of a 10% glucose solution; 3) when administered ICV (1 and 2 mg/animal) and IV (2 mg/kg) it delayed the gastric emptying of the solid meal.47290-

Effect of on phenyl pyrazolones derivatives on gastric emptying of liquid emptying in rats

Orientador: Edgard Ferro CollaresTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O esvaziamento gástrico (EG) é um processo de transferência do conteúdo gástrico para o intestino delgado, resultante da ação de mecanismos inibidores e estimuladores que controlam a atividade motora do estômago, piloro e duodeno. A dipirona, um derivado da fenilpirazolona, por via intravenosa (iv) e intra-cérebro-ventricular (icv), em ratos, retarda o esvaziamento gástrico (EG) de uma refeição líquida (salina). Quando administrada por via iv, o fenômeno foi abolido pela vagotomia sub-diafragmática e lesão eletrolítica do núcleo para-ventricular do hipotálamo. Em observação adicional, foi demonstrado que este efeito foi bloqueado pela injeção icv de baclofen, um agonista de receptores GABAB. O derivado fenilpirazolônico antipirina injetado iv também retarda o EG de líquido e este efeito foi reduzido significativamente pela vagotomia sub-diafragmática e abolido pela injeção icv de baclofen. Adicionalmente, demonstramos que a administração iv de 4-aminoantipirina (um metabólito da dipirona) diminui o EG de líquido em ratos e, da mesma forma que com a antipirina, foi reduzido significativamente pela vagotomia sub-diafragmática e abolido pela injeção icv de baclofen. Em situações em que há alteração no EG, a participação do estômago no processo pode ser inferida através da determinação in vivo do volume e da complacência gástrica, como indicadores do tônus gástrico. O tônus desta região é resultado, em grande parte, da atividade do nervo vago. Demonstramos que, para as condições de estudo as três drogas aumentam a complacência gástrica. O conjunto destes estudos sugere a participação do sistema nervoso central (SNC) e do nervo vago no fenômeno de retardo do EG induzido por estas drogas. Como somente a dipirona induziu o mesmo efeito quando administrada icv e o retardo do EG induzido pelas três drogas iv foi abolido pela vagotomia sub-diafragmática, em continuidade especulamos que o estímulo inibitório do EG, quando da administração por via iv, chegue ao SNC através de vias aferentes. A capsaicina é uma neurotoxina que administrada a ratos recém nascidos resulta em degeneração irreversível da maioria dos neurônios aferentes periféricos com axônios não mielinizados (fibras C) e de uma minoria de fibras escassamente mielinizadas (fibras A?). Constatamos que a administração desta neurotoxina, no período neonatal, a ratos, aboliu o efeito destas três drogas administradas iv, mas não da dipirona icv, sugerindo a participação das vias aferentes no fenômeno e de que o mecanismo (ou mecanismos) envolvido no efeito da administração dipirona no SNC difere daquele quando a droga é administrada iv. Embora os estudos relacionados ao efeito dos derivados fenilpirazolônicos sobre o EG, indicarem a participação do nervo vago no fenômeno, sabe-se que os efeitos do sistema nervoso simpático e parassimpático sobre os sistemas podem ser sinérgicos, exclusivos e até mesmo concomitantes. O sistema nervoso simpático, que tem efeito inibitório sobre o EG, libera norepinefrina nas terminações pós-ganglionares. Foram identificados subtipos de "alfa"- e ß-adrenoceptores em diferentes níveis do trato gastrointestinal que podem ter participação importante no controle da motricidade gástrica. Há evidências que neurônios aferentes e eferentes do nervo vago possuam beta-adrenoceptores, sendo que o subtipo ß2-adrenoceptor parece ser o predominante. Avaliando a participação do sistema adrenérgico no retardo do EG, os resultados do estudo sugerem: 1) que a simpatectomia química ou o pré-tratamento com propranolol (antagonista não seletivo ß-adrenérgico) aboliram o efeito da dipirona e antipirina e reduziram o da 4-aminoantipirina sobre o EG; 2) como pouco provável que retardo do EG induzido por estas drogas ocorra por ativação de "alfa"1-, "alfa"2-, ß1- , ß2- e ß3-adrenoceptores periféricos. Estes últimos resultados aventam a possibilidade que no efeito destas drogas haja envolvimento da ativação de receptores ß1- e/ou ß2-adrenérgicos no SNC e, que o mesmo, não ocorra em grande parte do efeito da 4-aminoantipirinaAbstract: Gastric emptying (GE) is the process of transfer of the gastric contents to small intestine, as result of inhibitory and stimulatory mechanisms that control the stomach, pylorus and duodenum motor activity. Dipyrone, a phenylpyrazole derivative, administrated intravenously (iv) and intracerebroventricularly (icv), in rats, slows the gastric emptying (GE) of a liquid meal (saline). When administrated iv, this phenomenon was abolished by sub-diaphragm vagotomy and electrolytic lesion of the hypothalamus paraventricular nucleus. In an additional study, it was demonstrated that this effect was blocked by icv injection of baclofen, a GABAB receptor agonist. The phenylpyrazole derivative antipyrine when injected by iv slows the GE of liquid also, and this effect was significantly decreased by sub-diaphragm vagotomy and abolished by bacloflen icv injection. Moreover, we demonstrated that the 4-aminoantipyrine (a dipyrone metabolite) administration iv decrease the GE of liquids in rats and as antipyrine, it was significantly reduced by subdiaphragm vagotomy and abolished by bacloflen icv injection. When happen alterations on GE, the stomach activity in this process can be inferred by in vivo determination of gastric volume and complacency, as indicators of gastric tone. The tone of this region is a result, mostly, of vagus nerve activity. We showed that in our studies conditions, the three drugs increased gastric complacence. Putting these results together we suggested the action of central nervous system (CNS) and vagus nerve in the GE retardation induced by these drugs. Taking into account that only dipyrone induced the same effect when administrated icv and that GE retardation induced by the three drugs was abolished by sub-diaphragm vagotomy, we speculated whether the GE inhibitory stimulus, when the drugs were administrated iv, reach the CNS through afferent pathway. The capsaicin is a neurotoxin which when administrated to new born rats, results in irreversible degeneration of the most part of peripheral afferent neurons with unmyelinated axons (fiber C) and a minority of thinly myelinated fibers (fiber A"sigma"). Our studies showed that the administration of this neurotoxin, during neonatal period, nullify the effect of these three drugs when administrated by iv, but didn't when dipyrone was gave by icv, what suggests the role of afferent pathways in this phenomenon and that the mechanism (or mechanisms) involved in the effect of dipyrone administration on CNS id different when the drug is administrated by iv. Although the studies related to phenylpyrazole derivative effects on the GE indicated the action of vagus nerve on this phenomenon, we know that the effects of sympathetic and parasympathetic system on the systems can be synergics, exclusives and to concomitant. The sympathetic nervous system, which has inhibitory effect on the GE, releases norepinephrine in the postganglionic endings. It was identified subtypes of "alfa"- and ß- adrenoreceptors in different sites in gastrointestinal tract that may have important roles in the control of gastric motor. It's evidences that afferent and efferent neurons of vagus nerve have beta-adrenoreceptors and the subtype ß2-adrenoreceptor seems to be the predominant. Evaluating the participation of adrenergic system on the GE retardation, the results of our study suggest: 1) the chemistry sympathectomy or the early treatment with propanolol (ß-adrenergic non selective antagonist) abolished the effect of dipyrone and antipyrine and reduced the effect of 4-aminoantipyrine on the GE; 2) it's almost unlikely that the slow GE induce by these drugs occur by activation of "alfa"1-, "alfa"2-, ß1- , ß2- e ß3- peripherics adrenoreceptors. The last results suggest the possibility that in this drugs effects have involvement of receptor ß1- and/or ß2-adrenergics activation on the CNS and that this don't occur at mostly of 4-aminoantipyrine effectDoutoradoDoutor em Farmacologi

Antiulcerogenic effect of Chlorella vulgaris extract

Orientadores: Edgard Ferro Collares, Alba Regina Monteiro Souza BritoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: A úlcera péptica acomete cerca de 10% da população mundial; inseridos dentro dessa porcentagem estão milhares de brasileiros. Essa patologia é causada por um desbalanço entre os mecanismos protetores e agressores da mucosa, e é resultado da associação de diversos fatores agressores endógenos (ácido, pepsina e bile), fatores exógenos predisponentes às condições de vida (estresse, fumo, álcool, uso continuo de drogas antiflamatórias não esteróides, ingestão de determinados alimentos e a presença do Helicobacter pylori) e a predisposição genética. Atualmente, as terapêuticas utilizadas no tratamento das lesões são: antiácidos, anticolinérgicos, antagonistas de receptores H2 para histamina, inibidores da bomba de próton, antibióticos e mais raramente alguns procedimentos cirúrgicos. A aplicação de qualquer esquema terapêutico com emprego de uma ou mais destas drogas ou procedimento cirúrgico pode ocasionar alguns efeitos colaterais e não obrigatoriamente é eficaz. A utilização de plantas medicinais no tratamento de doenças vem se desenvolvendo na última década. Algumas plantas têm atividade antiulcerogênica. Há evidências que a alga Chlorella vulgaris pode modificar a resposta imune celular, tem atividade antitumoral, antimetastática e antiulcerogênica. O objetivo do presente estudo foi avaliar a atividade antiulcerogênica da alga Chlorella vulgaris em modelos agudos e um modelo crônico de indução de úlceras. Ratos Wistar foram utilizados para determinação do esvaziamento gástrico (EG) e modelos de úlcera induzida por etanol e ácido acético, enquanto camundongos swiss foram utilizados para os modelos de úlcera através de ligadura do piloro e piroxicam. Para avaliar o efeito sobre o esvaziamento gástrico (EG) do extrato de Chlorella vulgaris (ECV) foi utilizada uma refeição de prova (RP) liquida com extrato nas concentrações de 50mg/mL e 100mg/mL do ECV. Para o estudo dos modelos agudos de ligadura do piloro, etanol e piroxicam e do modelo crônico, foram utilizadas as doses de 250, 500 e 1000mg/kg de ECV para a prevenção e o tratamento das lesões. No modelo crônico também foi utilizada a fração acetato obtida do ECV na dose de 5mg/100g e foi dosada a quantidade de fator de crescimento epidermal (EGF) produzido na região da úlcera. O estudo da toxicidade do ECV foi realizado através da medida de ganho de peso dos ratos e peso dos órgãos como rins, pulmões, fígado e coração, visto que os primeiros sinais da toxicidade dada por um extrato é a perda de peso corporal e dos órgãos.O ECV, nas concentrações empregadas, não interferiu no EG quando preparado como uma RP liquida em comparação com o veículo (água). O extrato não alterou nenhum dos parâmetros bioquímicos como pH, quantidade de H+ e peso do suco gástrico, no modelo de ligadura do piloro. O ECV não preveniu a formação de úlceras no modelo de piroxican, mas evitou a formação de lesões causadas por etanol nas doses de 500 e 1000 mg/kg. Esse efeito desapareceu quando o etanol foi empregado duas horas após o pré-tratamento com ECV na dose de 1000 mg/kg. No modelo de úlcera crônica o ECV, nas doses de 500 e 1000 mg/kg, foi capaz de diminuir significativamente as lesões causadas pelo ácido acético, não alterando no entanto, a quantidade de EGF produzida na zona de cicatrização, quando comparados ao controle água. Além disso, o tratamento prolongado com o ECV na dose de 500 mg/kg alterou significativamente a evolução do ganho de peso desses animais. Em conclusão, o ECV, como complemento alimentar, pode ser uma alternativa no tratamento da úlcera péptica gástricaAbstract: About 10%of the world¿s population suffer from peptic ulcer, within this percentage we find thousands of Brazilians. This pathology is caused by an unbalance between the protection and attack mechanisms of the stomach lining, and is the result of the association of various endogenous attack factors (pepsin, acid, bile), exogenous factors pertaining to life style (stress, smoking, alcohol intake, continuous use of non-steroidal anti-inflammatory drugs, ingestion of certain types of food and the presence of Helicobacter Pylori) and genetic predisposition. Nowadays, the therapeutic methods used for the treatment of the lesions are: Anti-acids, anti-cholinergic, antagonist H2 receptors for histamine, proton bombs; certain surgical procedures are also applied, though much less frequently. Any therapeutic method that involves the use of one or more of the drugs and/or procedures above mentioned may cause some side effects and is not necessarily effective. The use of medicinal plants in the treatment of diseases has been developing over the past decade. Some plants have an anti-ulcer activity. There is evidence that the Chlorella vulgaris algae may modify cellular immune response, and there is also evidence to its anti-tumor, anti-metastasis, anti-ulcer activity. The objective of this present study was to evaluate the anti-ulcer activity of the Chlorella vulgaris algae acute models of ulcer induction and also in one chronic model of ulcer induction. Wistar rats were used to determine gastric emptying (GE) and in models of ulcer induced by ethanol and acetic acid, while swiss mice were used for the piloro ligature and piroxicam ulcer induction models. In order to evaluate the effect of the Chlorella vulgaris extract (ECV) on gastric emptying (GE) a liquid proof meal (PM) with the extract in the concentration of 50mg/l and 100mg/l was usedIn the study of the acute piloro ligature, ethanol and piroxicam models, and in the chronic model, dosages of 250, 500 and 1000mg/kg of ECV were used in the prevention and treatment of the lesions. In the chronic model the fraction of acetate obtained from the ECV in the dosage of 5mg/100g was also used, and the amount of epidermal growth factor (EGF) produced in the region of the ulcer was measured. The toxicity study of the ECV was done by measuring the weight gain of the rats and the weight of their organs i.e. kidneys, lungs, liver, and heart, once the first signs of toxicity by an extract are loss of body and organ weight. The ECV, in the concentration used, did not interfere with the GE when prepared as a liquid PM in comparison to the vehicle (water). The extract did not alter any of the biochemical parameters such as pH, amount of H+ and weight of the gastric juice in the piloro ligature model. The ECV did not prevent the formation of ulcer in the piroxicam model, but it prevented the formation of lesions caused by ethanol in the dosage of 500 and 1000mg/kg. This effect disappeared when ethanol was ministered two hours after the pre-treatment with ECV in the dosage of 1000mg/kg. The chronic ulcer induction model the ECV, in the dosage of 500 and 1000mg/kg, was able to significantly lessen the lesions caused by acetic acid, not altering, however, the amount of EGF produced in the scar tissue area when compared to the water control. Furthermore, the long-term treatment with ECV in the dosage of 500mg/kg significantly altered the evolution of weight gain of these animals. In conclusion, the ECV, as a dietary complement, may be an alternative in the treatment of gastric peptic ulcerMestradoFisiologiaMestre em Biologia Funcional e Molecula

[the Effect Of Bacterial Lipopolysaccharide On The Gastric Emptying Of Rats: A Pretreatment Evaluation Using Nw-nitro-l-arginine Methyl Ester (l-name)].

There is evidence that nitric oxide plays a role in the decrease in gastric emptying induced by bacterial lipopolysaccharide. To evaluate the effect of pretreatment with Nw-nitro-L-arginine methyl to ester, one competitive inhibitor of the nitric oxide synthases, on the gastric emptying delay induced by lipopolysaccharide. Male Wistar rats, SPF, were used after 24 h fast and 1 h-water withdrawn. The pretreatment was done intravenously with vehicle (saline) or N(w)-nitro-L-arginine methyl to ester in the doses of 0.5, 1, 2.5 e 5 mg/kg. After 10 min, the animals were treated iv with lipopolysaccharide (50 microg/kg) or received vehicle (saline). The gastric emptying was evaluated 1 h after the lipopolysaccharide administration. A saline solution containing phenol red was used as the test meal. The gastric emptying was indirectly assessed by the determination of percent gastric retention of the test meal 10 min after orogastric administration. The animals pretreated with vehicle and treatment with lipopolysaccharide have significant rise of the gastric retention (average = 57%) in comparison with the controls receiving only vehicle (38.1%). The pretreatment with the different doses of N(w)-nitro-L-arginine methyl to ester did not modify per se the gastric retention in comparison with the animals pretreated with vehicle. Pretreatment with N(w)-nitro-L-arginine methyl to ester with the dose of 1 mg/kg determined a discrete but significant reduction in the gastric retention (52%) of animals treated with lipopolysaccharide in comparison with vehicle-pretreated rats. Paradoxically, animals pretreated with 2.5 or 5 mg of N(w)-nitro-L-arginine methyl to ester/kg followed by treatment with lipopolysaccharide displayed a significantly higher gastric retention (74.7% and 80.5%, respectively) as compared to their controls, pretreated with the same doses of the inhibitor and treated with vehicle (40.5% and 38.7%, respectively) and to those pretreated with vehicle and treated with the same toxin. The pretreatment with N(w)-nitro-L-arginine methyl to ester at low dose (1 mg/kg) resulted in a discrete inhibition of the gastric emptying delay induced by lipopolysaccharide. Nevertheless, N(w)-nitro-L-arginine methyl to ester at higher doses (2.5 and 5 mg/kg) induced an enhancement of the lipopolysaccharide effect on gastric emptying, despite not interfering with the gastric emptying per se.43229-3

[the Effect Of Bacterial Lipopolysaccharide On The Gastric Emptying Of Rats: A Pretreatment Evaluation Using Dexamethasone And Methylene Blue].

The nitric oxide might be a putative mediator of the decrease in gastric emptying induced by bacterial lipopolysaccharide in rats. For that, we evaluated the effect of the pretreatment intravenous with dexamethasone and methylene blue in the retardation process of gastric emptying induced by intravenous application of lipopolysaccharide in rats. Dexamethasone has been shown to inhibit the induction of NOS II (induced NO-synthase) while the methylene blue, that blocks the soluble guanylyl cyclase, inhibits nitric oxide synthases and, in addition, inactivates nitric oxide directly. Male Wistar rats, specific patogenic free, were used after a 24 hour fast and 1 hour-water withdrawn. The pretreatment was performed using dexamethasone solutions (3 and 6 mg/kg), methylene blue (2 mg/kg) or sterile vehicle. The treatment consisted in the application of lipopolysaccharide (50 mug/kg) or vehicle. The time period between the pretreatment and treatment was 10 minutes, excluding the study with dexamethasone 6 mg/kg that was 1 hour. The gastric emptying was evaluated 1 hour after the lipopolysaccharide application, except for two studies with dexamethasone 3 mg/kg in which the time periods were 2 and 8 hours. A saline solution containing phenol red was used as the test meal. The gastric emptying was determined by measuring gastric retention 10 minutes after the orogastric infusion of the test meal. The pretreatment with dexamethasone or methylene blue and treatment with vehicle did not have effect in the gastric emptying comparing to the control group. We found that pretreatment with dexamethasone in the studies for 1 hour and 2 hours did not interfere in the retardation of the gastric emptying produced by endotoxin. Nevertheless, in the eighth period study with this drug there was a significant reduction of gastric retention in the endotoxin-treated animals in relation to the unpretreated ones. Meanwhile, the pretreatment with the methylene blue completely blocked the action of endotoxin on the gastric emptying in rats. These results suggest a possible involvement of nitric oxide on the effect of lipopolysaccharide in rat gastric emptying.40104-

Efeito do lipopolissacarídio bacteriano sobre o esvaziamento gástrico de ratos: avaliação do pré-tratamento com dexametasona e azul de metileno

RACIONAL: O óxido nítrico pode estar envolvido no retardo do esvaziamento gástrico produzido pelo lipopolissacarídio bacteriano. OBJETIVO: Avaliar o efeito do pré-tratamento com a dexametasona, bloqueadora da indução do óxido nítrico-sintetase induzida e com o azul de metileno, que bloqueia a guanilato-ciclase, inibe as óxido nítrico-sintetases e inativa o óxido nítrico, sobre o retardo do esvaziamento gástrico determinado pelo lipopolissacarídio em ratos. MATERIAL E MÉTODOS: Foram utilizados ratos Wistar, machos, ''specific patogen free'', após 24 horas de jejum alimentar. No pré-tratamento foram empregadas, via intravenosa, soluções de dexametasona (3 e 6 mg/kg), azul de metileno (2 mg/kg) e veículo estéril. O tratamento constou da administração, via intravenosa, de lipopolissacarídio (50 mig/kg) e veículo. O intervalo entre o pré-tratamento e o tratamento foi de 10 minutos, exceto no estudo com dexametasona 6 mg/kg, que foi de 1 hora. O intervalo entre a administração do lipopolissacarídio e a avaliação do esvaziamento gástrico foi de 1 hora, exceto nos dois estudos com dexametasona 3 mg/kg que foram de 2 e 8 horas. O esvaziamento gástrico foi avaliado, indiretamente, através da determinação da percentagem de retenção gástrica de solução salina marcada com fenol vermelho. RESULTADOS: Os valores de retenção gástrica, nos animais pré-tratados com dexametasona ou azul de metileno e tratados com veículo, não diferiram significativamente dos observados nos que receberam veículo nos dois momentos. Os animais pré-tratados com veículo e tratados com lipopolissacarídio apresentaram valores de retenção gástrica significativamente mais elevados que nos controles. O pré-tratamento com dexametasona não interferiu no aumento da retenção gástrica determinado pelo lipopolissacarídio, nas primeiras 2 horas após administração da endotoxina. Oito horas após a administração da endotoxina, foi observada diminuição significativa da retenção gástrica nos animais pré-tratados com dexametasona e tratados com lipopolissacarídio em relação aos que receberam veículo + lipopolissacarídio. O mesmo fenômeno foi observado nos animais pré-tratados com azul de metileno e tratados com lipopolissacarídio. CONCLUSÃO: Os resultados sugerem o envolvimento do óxido nítrico no efeito do lipopolissacarídio sobre o esvaziamento gástrico em ratos