Impaired gallbladder motility is an established factor stone disease may initially represent a metabolic liver in cholesterol gallstone formation. We assessed whether disorder but can be modulated by the enterohepatic altered small intestinal smooth muscle contractility with circulation of bile salts.2,9-14 The gallbladder (by filling slow transit might potentiate gallstone formation by fur-and emptying) and the small intestine (by governing ther impeding enterohepatic cycling of bile acids. transit time) are the rate-limiting steps that control Ground squirrels were fed a 1% or a trace (controls) cho-the enterohepatic cycling frequency of bile salts and lesterol diet. Small intestinal transit was evaluated from their flux through the liver. [9][10]14,15 Enterohepatic cy- size calculated by isotope dilution. Gas-liquid chromaProlonged small intestinal transit, like impaired tography (GLC) assessed bile salt profile. In animals on gallbladder emptying, should hinder enterohepatic cythe 1% cholesterol diet, aboral transit was significantly cling and lower the bile salt secretion rate, thus predisdelayed, the maximal contractile response to betha-posing to the formation of gallbladder bile saturated nechol was markedly increased (P õ .05) with no change with cholesterol.9,10,14 Recent studies of cholesterol gallin median effective concentration in either circular or stone pathogenesis in nonobese subjects and in acromelongitudinal muscle strips from both the jejunum and galic patients treated with the long-acting somatoileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. statin analog, octreotide, support and advance this Cholesterol saturation index and the fraction of deoxy-hypothesis. In each condition, either prolonged wholecholic acid in the pool doubled, whereas the total bile gut transit or lengthened small intestinal transit has salt pool size remained unchanged in cholesterol-fed an-been linked to an increased production of deoxycholate, imals. In this model, a high-cholesterol diet is associated saturated gallbladder bile, and the subsequent formawith altered small intestinal smooth muscle contractility tion of cholesterol gallstones. [16][17][18] The importance of the

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In the Hooded-Lister rat model, food protein induced intestinal anaphylaxis disrupts the migrating motor complex (MMC) and causes an increased frequency of migrating clusters of contractions (MCCs, including giant migrating contractions (GMCs)) and diarrhea. To determine whether mast cell mediators act on enteric neurons to initiate these alterations in motility, rats were sensitized by intraperitoneal injection of 10 micrograms egg albumin (antigen (Ag)). Seven days later two jejunal manometry catheters were implanted 2.5 cm apart. On day 14, motility was recorded in fasted rats before and after intraluminal challenge with 10 mg Ag in 0.5 mL saline, both without and after pretreatment by specific antagonists. Ag challenge of sensitized animals disrupted MMCs and caused an increase in total MCCs (including GMCs) and diarrhea. Atropine or hexamethonium abolished all intestinal motility, including Ag-induced MCCs, GMCs, and diarrhea. At higher doses, agents that inhibit mast cell degranulation, cromoglycate, doxantrazole, and quercetin, did inhibit Ag-induced MCCs, GMCs, and diarrhea, but at the expense of inhibiting normal intestinal motility. Cimetidine and diphenhydramine together inhibited normal cycling of the MMC, but did not abolish Ag-induced MCCs, GMCs, and diarrhea. Methysergide was ineffective, but cinanserin and WAY 100,289 significantly inhibited, and indomethacin most effectively blocked, the Ag-induced disruption of MMCs and the increase in MCCs, GMCs, and diarrhea. Thus, the altered motility and the diarrhea observed after food protein induced luminal challenge of sensitized rats is dependent upon myenteric neuronal circuitry. The mast cell stabilizers doxantrazole and quercetin block the response because of a nonspecific anticholinergic effect. Cinanserin and WAY 100,289 partially inhibit, and indomethacin most effectively blocks, the response, suggesting that activated mast cells release prostaglandins and perhaps 5-hydroxytryptamine, which stimulate the neuronal pathway.

Lipopolysaccharide (LPS)-induced intestinal endotoxaemia perturbs motility and causes activation and influx of inflammatory cells into the muscle tissue. Because rat submandibular gland peptide T (SGP-T; Thr-Asp-Ile-Phe-Glu-Gly-Gly), its carboxyl-terminal fragment tripeptide, FEG (Phe-Glu-Gly) and its D-isomeric analogue, feG, modulate intestinal anaphylactic reactions, we examined whether these peptides also modulate LPS-induced intestinal endotoxaemia in conscious rats. The disruption of the fasting pattern of intestinal MMCs (migrating motor complexes), induced by intravenous LPS (20 microg kg-1) injection, was prevented by all three peptides. The extravasation of leucocytes into the peritoneal cavity and increased expression of the activation marker CD18 on mesenteric tissue leucocytes (18 h after intraperitoneal injection of LPS) were reduced by orally administered feG, which also significantly decreased the number of intestinal tissue leucocytes expressing the integrin CD18. We conclude that feG attenuates both the immediate (intestinal motility) and late ( approximately 18 h) inflammatory reactions provoked by endotoxaemia.

The roles of mast cells and extrinsic and vagal neural pathways in the anaphylaxis-induced alterations in motility observed at sites remote from antigen exposure were explored. Rats were sensitized to egg albumin (EA) and prepared with 1) electrodes to monitor intestinal myoelectric activity, 2) an isolated intestinal loop, and 3) either intact vagal innervation or a subdiaphragmatic vagotomy. Fasting myoelectric activity was recorded before and after challenge of the jejunum in continuity or the isolated loop with EA or BSA. Intestinal segments and the brain stems were processed for mast cell identification (intestine) or Fos immunoreactivity (brain stem). EA but not BSA challenge of the jejunum or the isolated loop induced altered motility at both sites and diarrhea. Granulated mast cells were significantly reduced at the site local to but not remote from challenge. Vagotomy did not inhibit antigen-induced alterations in motility or diarrhea. The number of Fos-immunoreactive nuclei in vagal sensory or motor nuclei was not significantly altered by vagotomy. Thus antigen challenge of sensitized animals causes mast cell degranulation only at the site of direct challenge but alters motility at sites local and remote from challenge. The remote response requires intact extrinsic but not necessarily vagal neural pathways.