RESUMO
prevents, in pancreocytes, the evolving of a "supramaximalecbolic-stimulation" process. The PP involvement as a modulating agent of pancreon's reactivity is reflected by the progressive increment of its plasma values in the first week of an evolving AP episode. In the AP associated to a large meal, an overpowering of the pancreon's brake might have a pivotal role. In experimental and clinical chronic alcoholism, a vagal neuropathy of the Pavlov inhibitory fibers that, as a consequence, impairs the pancreon's brake through a depression of PP secretion is at the basis of an enhanced reactivity of the duodeno-pancreatic reflexes. The latter leads to intrapancreatic cholinergic hypertonus and to Vater papilla's dysfunction. These changes, plus an enhanced pancreocyte's response to CCK, are at the core of acinar cell "supramaximal stimulation" with the organelle disruption that process implies. The intrapancreatic cholinergic hypertonus, the enhanced exocrine cell reactivity to CCK stimulation, and the augmented resistance to the pancreatic secretion flow at Oddi sphincter, explain the aggravating influence of chronic alcoholism on an episode of acute biliary pancreatitis. As the PP secretion, normally elicited by secretin, CCK, food and insulin hypoglycemia, is depressed in the presence of an augmented number of PP cells, as it is in the cases of chronic alcoholics, cystic fibrosis patients and, also, in dogs with pancreatic fibrosis (ductal ligation), it has been inferred, besides our postulated impairment of the Pavlov inhibitory fibers in the vagus nerves, that the defect of PP release is localized to the common final pathway of the above stimuli, probably in or near the PP cell itself This review was prompted by the unexpected experimental finding in canines that Tissucol-induced pancreatic ductal blockade elicits Pancreatic Polypeptide (PP) release and seems to be at the basis of the beneficial effects on taurocho- late-induced acute pancreatitis (AP). In the release mechanism of this regulatory peptide secreted by PP cells located in the periphery of Langerhans islets and scattered in the ductal epithelium, two neuroendocrine reflexes (NER) are involved. The "short" NER is evoked from the duodenum by an unknown component of bile-pancreatic secretion. The "long" NER is triggered by a vagovagal reflex. PP induces a depression of the intrapancreatic cholinergic tone. On the one hand suppressing, hormonally, nervous impulses discharge from the vagal nuclear complex in the brainstem. On the other, interfering paracrinically on the cholinergic transmission by acting, presynaptically, on post-ganglionic cholinergic neurons. The resulting PP-evoked fall of the intrapancreatic cholinergic tone depresses the hormone induced (secretin, CCK) pancreons secretory response. PP, with other agents, contributes to the "fail-safe" system or pancreon's brake that
Assuntos
Etanol/toxicidade , Ilhotas Pancreáticas/metabolismo , Sistemas Neurossecretores/efeitos dos fármacos , Pâncreas Exócrino/metabolismo , Polipeptídeo Pancreático/metabolismo , Animais , Cães , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Pâncreas Exócrino/efeitos dos fármacos , Polipeptídeo Pancreático/efeitos dos fármacos , ReflexoRESUMO
OBJECTIVE: We sought to evaluate the effects of telmisartan, sitagliptin, or their combination on pancreatic ultrastructural alterations in high-fat-fed C57BL/6 mice. METHODS: Three-month-old C57BL/6 mice were fed with standard chow (SC, 10% lipids) or high-fat diet (HF, 60% lipids) during 10 weeks to induce obesity and its comorbidities. After this period, treatment began (lasted 6 weeks), and the HF group was divided into 4 subgroups: untreated HF, HF plus telmisartan (5 mg/kg per day), HF plus sitagliptin (1.1 g/kg per day), and HF plus telmisartan plus sitagliptin. Drugs were mixed with diet. Biochemical analyses, radioimmunoassay, immunofluorescence, stereology, and transmission electron microscopy were performed to assess pancreatic remodeling. RESULTS: Overweight, hyperinsulinemia, hyperglycemia, and dyslipidemia were found in the HF group, but these outcomes were controlled by the different treatments. Untreated HF animals also showed alterations concerning distribution of α/ß cell followed by large and numerous lipid droplets within pancreas. Telmisartan and sitagliptin as monotherapy alleviated these findings, and a complete reversal of pancreatic steatosis was observed after treating with the combination of the 2 drugs. CONCLUSIONS: AT1 receptor blockade, partial peroxisome proliferator-activated receptor gamma activation, and extended incretin action emerge as feasible strategies to control pancreatic steatosis and avoid progression of pancreatic diseases due to lipotoxicity.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Benzimidazóis/administração & dosagem , Benzoatos/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Obesidade/tratamento farmacológico , Obesidade/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/ultraestrutura , Pirazinas/administração & dosagem , Triazóis/administração & dosagem , Animais , Glicemia/metabolismo , Gorduras na Dieta/administração & dosagem , Quimioterapia Combinada , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/ultraestrutura , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Pâncreas/metabolismo , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/ultraestrutura , Fosfato de Sitagliptina , TelmisartanRESUMO
AIM: To investigate chronic stress as a susceptibility factor for developing pancreatitis, as well as tumor necrosis factor-α (TNF-α) as a putative sensitizer. METHODS: Rat pancreatic acini were used to analyze the influence of TNF-α on submaximal (50 pmol/L) cholecystokinin (CCK) stimulation. Chronic restraint (4 h every day for 21 d) was used to evaluate the effects of submaximal (0.2 µg/kg per hour) cerulein stimulation on chronically stressed rats. RESULTS: In vitro exposure of pancreatic acini to TNF-α disorganized the actin cytoskeleton. This was further increased by TNF-α/CCK treatment, which additionally reduced amylase secretion, and increased trypsin and nuclear factor-κB activities in a protein-kinase-C δ and ε-dependent manner. TNF-α/CCK also enhanced caspases' activity and lactate dehydrogenase release, induced ATP loss, and augmented the ADP/ATP ratio. In vivo, rats under chronic restraint exhibited elevated serum and pancreatic TNF-α levels. Serum, pancreatic, and lung inflammatory parameters, as well as caspases'activity in pancreatic and lung tissue, were substantially enhanced in stressed/cerulein-treated rats, which also experienced tissues' ATP loss and greater ADP/ATP ratios. Histological examination revealed that stressed/cerulein-treated animals developed abundant pancreatic and lung edema, hemorrhage and leukocyte infiltrate, and pancreatic necrosis. Pancreatitis severity was greatly decreased by treating animals with an anti-TNF-α-antibody, which diminished all inflammatory parameters, histopathological scores, and apoptotic/necrotic markers in stressed/cerulein-treated rats. CONCLUSION: In rats, chronic stress increases susceptibility for developing pancreatitis, which involves TNF-α sensitization of pancreatic acinar cells to undergo injury by physiological cerulein stimulation.
Assuntos
Pâncreas Exócrino/imunologia , Pancreatite/psicologia , Estresse Psicológico/complicações , Fator de Necrose Tumoral alfa/metabolismo , Actinas/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Amilases/metabolismo , Animais , Anticorpos/farmacologia , Sinalização do Cálcio , Caspases/metabolismo , Ceruletídeo , Colecistocinina/metabolismo , Doença Crônica , Citoesqueleto/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Lesão Pulmonar/etiologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/psicologia , Masculino , NF-kappa B/metabolismo , Necrose , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/patologia , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Pancreatite/metabolismo , Pancreatite/patologia , Pancreatite/prevenção & controle , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-épsilon/metabolismo , Transporte Proteico , Ratos , Ratos Wistar , Restrição Física , Índice de Gravidade de Doença , Técnicas de Cultura de Tecidos , Tripsina/metabolismo , Fator de Necrose Tumoral alfa/imunologiaRESUMO
We previously reported that C-type natriuretic peptide (CNP) increases amylase release in isolated pancreatic acini through natriuretic peptide receptor C activation and enhances pancreatic exocrine secretion via vagal pathways when applied to the brain. In the present study we sought to establish whether CNP was involved in the peripheral regulation of pancreatic secretion. Anesthetized rats were prepared with pancreatic duct cannulation, pyloric ligation and bile diversion into the duodenum. CNP dose-dependently enhanced pancreatic flow, chloride and protein excretion but did not modify bicarbonate output. A selective natriuretic peptide receptor C agonist enhanced pancreatic flow and mimicked CNP-evoked protein output but failed to modify chloride secretion. Truncal vagotomy, perivagal application of capsaicin and hexamethonium reduced CNP-evoked pancreatic flow and abolished chloride excretion but did not affect protein output. Furthermore, pre-treatment with atropine reduced both CNP-stimulated pancreatic flow and chloride excretion but failed to modify protein excretion. Partial muscarinic blockade of CNP-evoked chloride output suggested that mediators other than acetylcholine were involved. However, CNP response was unaltered by cholecystokinin and vasoactive intestinal peptide receptor blockade or by nitric oxide synthase inhibition. In conclusion, CNP-stimulated pancreatic flow through the activation of the natriuretic peptide receptor C and the vago-vagal reflex but it increased protein output only by natriuretic peptide receptor C activation and chloride excretion by vago-vagal reflexes. Present results suggest that CNP may play a role as a local regulator of the exocrine pancreas.
Assuntos
Peptídeo Natriurético Tipo C/farmacologia , Pâncreas Exócrino/inervação , Pâncreas Exócrino/metabolismo , Nervo Vago/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Bicarbonatos/metabolismo , Cloretos/metabolismo , Colecistocinina/fisiologia , Relação Dose-Resposta a Droga , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Óxido Nítrico/fisiologia , Pâncreas Exócrino/efeitos dos fármacos , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do Fator Natriurético Atrial/agonistas , Estimulação Química , Nervo Vago/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/fisiologiaRESUMO
The present study evaluated the effects of the sweetener aspartame on the fetal pancreas, through a morphometric study, with the objective of studying the exocrine pancreas at the end of gestational development. For this we utilized two treated groups, one with a solution of aspartame at ambient temperature and the other with an aspartame solution heated to 40C, and two groups treated with water ad libitum, at ambient temperature and heated to 40C, respectively. On the final day of gestation the fetuses were removed and the pancreas was collected for microscopic analysis. The morphometric study demonstrated alteration in eight out of the eleven parameters studied in the group treated with the heated solution and one parameter altered in the group treated with solution at ambient temperature.
El presente estudio evalúa los efectos del endulzante aspartame en el páncreas fetal de rata, a través del estudio morfométrico, con el objetivo de conocer el páncreas exocrino al final del desarrollo gestacional. Fueron utilizados dos grupos tratados, uno con una solución de aspartame a temperatura ambiente y otro con una solución de aspartame calentada a 40C, y dos grupos tratados con agua ad libitum, a temperatura ambiente y calentada a 40 C, respectivamente. En el último día de gestación los fetos fueron removidos y el páncreas fue extraído para el análisis microscópico. El estudio morfométrico demostró alteraciones en ocho de los once parámetros estudiados en el grupo tratado con solución de aspartame calentada y un parámetro alterado en el grupo tratado con solución a temperatura ambiente.