RESUMEN
BACKGROUND: Chronic alcohol consumption increases the risk of pancreatitis in humans. Functional hyperstimulation/hypersecretion of the pancreas during chronic alcohol consumption appears to precede the onset of pancreatitis, and may contribute to the increased susceptibility to pancreatitis in alcoholics. However, the origin, nature and timing of hyperstimulation/hypersecretion are unknown. METHODS: Male Wistar rats were pair-fed ethanol liquid diet for 15-18 days (including one 9-day dose ramp-up phase) or regular liquid diets before placement of pancreatic, biliary, duodenal and venous catheters. Basal and stimulated pancreatic secretions were measured with or without acute alcohol infusion. Pancreatic secretion was stimulated with intravenous bethanechol, 2-deoxy-D-glucose (2-DG), cholecystokinin (CCK), octapeptide (CCK-8), intraduodenal meal, or vehicle. RESULTS: Acute alcohol potentiated 2-DG stimulated pancreatic secretion (184%, p < 0.05), whereas the response to CCK was unchanged, and the response to bethanechol was decreased (78%, p < 0.05). Short-term alcohol exposure lessened the exaggerated protein secretory response to 2-DG seen in acute alcohol exposure rats and increased the protein response to bethanechol (141%, p < 0.05), CCK (187%, p < 0.05) and meal (217%, p < 0.05). CONCLUSION: The pancreas is sensitive to acute alcohol ingestion with inhibition of acinar cell function. Rapid adaptation occurs with short-term alcohol feeding, resulting in an exaggerated response to cholinergic input at the acinar cells, plus disinhibition of CCK and meal-stimulated pancreatic secretion. The central response to 2-DG and CCK are similar to area postrema lesions. Adaptation appears to be in response to alcohol-associated inhibition of the neurohormonal stimulatory pathway and compensatory upregulation at the acinar cell level.
Asunto(s)
Adaptación Fisiológica/fisiología , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Páncreas Exocrino/efectos de los fármacos , Páncreas Exocrino/fisiología , Adaptación Fisiológica/efectos de los fármacos , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Antimetabolitos/farmacología , Betanecol/farmacología , Desoxiglucosa/farmacología , Duodeno , Ingestión de Alimentos , Inyecciones Intravenosas , Masculino , Modelos Animales , Agonistas Muscarínicos/farmacología , Páncreas Exocrino/metabolismo , Ratas , Ratas Wistar , Nervio Vago/fisiologíaRESUMEN
Chronic alcohol ingestion appears to increase susceptibility of the pancreas to pancreatitis through multiple mechanisms. The aim of the current study was to determine the effect of chronic low- and high-dose alcohol consumption on the neurohormonal control of the exocrine pancreas in rats. Male Wistar rats were fed Lieber DeCarli liquid control-, low-, and high-dose alcohol diets for 3 months. Pancreatic exocrine secretion was measured under basal and 2-deoxy-D-glucose (2-DG)-, CCK-, bethanechol-, or meal-stimulated conditions while on chronic alcohol diets and after 2-DG or CCK stimulation during alcohol withdrawal in awake rats. Chronic alcohol ingestion was associated with a dose-related inhibition of basal pancreatic protein secretion, which was reversed upon alcohol withdrawal. Low-dose alcohol feeding had no effect on bethanechol-stimulated pancreatic secretion but altered 2-DG-stimulated pancreatic secretion. In chronic high-dose alcohol rats, meal- and bethanechol-stimulated protein secretion was significantly potentiated during early and late phases. The response to CCK appeared to be disinhibited, whereas the response to 2-DG was uniformly blunted. Upon withdrawal of low-dose alcohol, the response to 2-DG was potentiated, whereas with the withdrawal of high-dose alcohol, the response to CCK was potentiated. Adaptation to chronic alcohol consumption differs depending on the alcohol dose. The most significant effects were seen after high-dose alcohol withdrawal, with apparent loss of central inhibitory regulation combined with exaggerated response at the acinar cell level. This combination of factors could increase susceptibility to acute alcoholic pancreatitis through a hyperstimulation mechanism.
Asunto(s)
Alcoholes/farmacología , Etanol/farmacología , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Animales , Betanecol/farmacología , Colecistoquinina/farmacología , Desoxiglucosa/farmacología , Alimentos , Fármacos Gastrointestinales/farmacología , Masculino , Modelos Animales , Páncreas/fisiopatología , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/fisiopatologíaRESUMEN
BACKGROUND: Identification and characterization of genes that are relevant to pancreatic cancer remains a priority for developing detection and diagnostic tests and identifying targets for treatment. MATERIALS AND METHODS: In order to discover relevant genes, we developed a microarray composed of 5763 pancreas and pancreatic cancer cDNA clones, representing genes of known and unknown function. The Pittsburgh Pancreas Enriched ARray (PittPEAR) was used to compare the gene expression differences between pancreatic cancer and normal pancreas. RESULTS: Two hundred and sixty-four genes were identified: 85 were overexpressed and 176 were underexpressed in cancer compared to normal tissue. Two of the top five genes included the cell cycle division 37 (CDC37) and period Drosophila homolog protein 1 (PER1), which play critical roles in cell division and transcriptional regulation, respectively. Underexpression of many genes probably reflected the loss of acinar and islet cells from the tumors. The biological functions of overexpressed genes include immune response genes, cytoskeletal and genes related to the extracellular matrix, cell invasion, migration, adhesion and motility. Apoptosis and transcription factor genes were also identified. CONCLUSION: We conclude that the PittPEAR microarray provides a useful tool for identifying genes that are relevant to the development and maintenance of pancreatic cancer.
RESUMEN
These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(-)-N-methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F = 4%) compared with the high oral bioavailability in dog (F = 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and N-demethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.