Constipation and fecal impaction are conditions of the bowel whose prevalence increases with age. Limited information is known about how these conditions manifest; however, functional deficits are likely to be due to changes in signaling within the bowel. This study investigated the effects of age on colonic mucosal melatonin (MEL) release and the consequences this had on colonic motility. Electrochemical measurements of MEL overflow demonstrated that both basal and mechanically stimulated MEL release decreased with age. The MEL/serotonin also decreased with increasing age, and the trend was similar to that of MEL overflow, suggestive that age-related changes were primarily due to a reduction in MEL levels. Levels of N-acetylserotonin and the N-acetylserotonin/serotonin ratio were reduced with age, providing an explanation for the reduction in MEL release. Decreases in colonic motility were observed in animals between 3 and 24 months old. Exogenous application of MEL could reverse this deficit in aged colon. In summary, we propose that the age-related decline in MEL release may be due to either decreases or alterations in mechanosensory channels and/or a loss in levels/activity of the N-acetyltransferase enzyme responsible for the synthesis of N-acetylserotonin. Decreases in MEL release may explain the decreases in colonic motility observed in 24 month old animals and could offer a new potential therapeutic treatment for agerelated constipation.

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Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.

Propofol is the most widely used intravenous anaesthetic agent for maintenance of anaesthesia and sedation. Studies in varying regions of the bowel have shown conflicting differences on the effects of propofol on motility. There the aim of this study was to understand the influence of propofol on colonic function and explore by which mechanism any changes occur. Functional studies were conducted using isolated colonic tissue from C57BL6 mice which were exposed to 5 µM propofol. Faecal pellet motility, colonic migratory motor complexes (CMMCs) and functional bioassays were utilised to monitor colonic function and nitric oxide production was monitored by amperometry. There was a signficant reduction in amplitude of CMMCs in the distal colon in the presence of 5 µM propofol, however no difference was observed in the proximal colon. A signficant increase in the 5-HT evoked contractions were observed in distal colon in the presence of 5 µM propofol. Additionally, a reduction in the NO production in the presence of 5 µM propofol was only observed in the in the distal colon. As a result, in the presence of 5 µM propofol, faecal pellet transit was increased, and velocity was reduced. At clinically relevant doses, propofol was shown to reduce colonic motility by inhibiting nitric oxide synthase in only the distal region of the colon.Our findings indicate that propofol has a considerable influence on colonic signalling mechanisms and impairs colonic motility, which may have implications in its clinical use especially for maintenance.

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