Undernournishment and Yersinia enterocolitica enterocolitis alter intestinal contractility in the rabbit: role of smooth muscle contractile protein content.

Previous studies have demonstrated that the longitudinal smooth muscle of rabbits infected with Yersinia enterocolitica and undernourished because of reduced food intake exhibit a significantly reduced ability to develop tension in response to carbachol compared with pair-fed animals, which are uninfected but equivalently undernourished. To determine whether the alteration in smooth muscle contractility results from changes in cell number (hypo- or hyperplasia), or in contractile protein content or isoform distribution, New Zealand White rabbits (600 to 1000 g) were randomly assigned to one of three treatment groups: infected, pair-fed or control. Tissue contractility was measured, morphometric studies were performed and immunoassays were developed for the measurement of total actin, gamma-enteric and alpha-vascular isoactins, and myosin heavy chain. Consistent with what was found in previous reports, the contractility of longitudinal smooth muscle in response to carbachol was found to increase in pair-fed animals and to decrease in Y enterocolitica-infected animals. There was no significant change in the proportional thickness of the ileal longitudinal smooth muscle coat, and the number of cross-sectioned longitudinal smooth muscle cells/mm2 was not significantly different in infected, pair-fed or control tissues. Immunoassay indicated that the proportion of each specific contractile protein, relative to total protein content in the muscularis propria, was unaffected by Y enterocolitica infection or by pair-feeding. Thus, the alterations in intestinal longitudinal smooth muscle function observed after Y enterocolitica infection were concluded not to be associated with tissue hypo- or hyperplasia, or changes in the total content or isoform distribution of contractile proteins in the muscularis propria.

Inflammatory mediators in gastrointestinal defense and injury.

Irrespective of where ulceration occurs in the gastrointestinal tract, it is almost always associated with mucosal inflammation. The chemical mediators that coordinate inflammatory responses also have the capability to alter the resistance of the mucosa to injury. Some inflammatory mediators increase the resistance of the mucosa to injury, while others exert "ulcerogenic" effects. In this review, we provide an overview of the major inflammatory mediators that have been shown to exert effects on mucosal defense in the gastrointestinal tract. Among the inflammatory mediators discussed are the eicosanoids (prostaglandins, leukotrienes, thromboxanes), nitric oxide, neuropeptides, and cytokines (IL-1beta, TNF alpha). Several of these mediators are considered potential therapeutic targets for the treatment of ulcerative diseases of the digestive system, and, in some cases, clinical data are available on the efficacy of such approaches.

Depressed smooth muscle contractility after massive intestinal resection in rat: role of alterations in muscarinic receptor status or source of calcium for excitation-contraction coupling.

Following massive intestinal resection (removal of 75% of the mid-jejunoileum) in the rat, there is a significant reduction in the in vitro tonic contractile response of the remaining jejunal circular smooth muscle in response to stimulation with the muscarinic agonist bethanechol. The aim of these experiments was to determine if this alteration is specific to muscarinic excitation and occurs as a result of changes in the source and availability of calcium required for excitation-contraction coupling, or reflects changes in muscarinic receptor number and (or) affinity. The contractile response of proximal jejunal circular muscle strips from sham-operated and resected rats was studied in vitro in response to electrical field stimulation, serotonin, and bethanechol, the later under conditions where extracellular calcium was absent or entry was excluded. In contrast with the significant reduction in tonic contractile response to muscarinic excitation of tissues from resected animals, there was an equivalent or enhanced response of these tissues to electrical field stimulation and serotonin, respectively. While sham-operated and resected groups showed similar dependency upon or availability of intracellular and extracellular calcium, the data indicate distinct pathways of calcium mobilization for tonic versus phasic contractile activity. Muscarinic receptor number and affinity were assessed by 1-quinuclidinyl[pheny1-4-3H]benzilate ([3H]QNB) binding to isolated smooth muscle cells and showed a significant increase in Bmax, with no change in Kd after resection. Thus, the reduced contractility of the circular muscle of the remnant jejunum after massive intestinal resection is a specific even associated with muscarinic receptor activation, but it is not the result of either an alteration in the source or availability of calcium required for excitation-contraction coupling or a reduction in the number and (or) affinity of muscarinic receptors.

Contractility of longitudinal smooth muscle after massive intestinal resection in rat.

To determine whether functional changes in contractility of jejunal longitudinal smooth muscle in vitro accompany the adaptive structural changes after massive intestinal resection, the investigators subjected rats either to surgical resection of 75% of the mid-jejuno-ileum or to a sham operation. The development of isometric tension in strips of jejunal tissue was measured 10, 20, 30 or 40 days after surgery. Basal stress in response to stretch was similar for both groups at all of the post-operative times. The optimal length (Lo) needed for the generation of maximal stress (130% of initial resting length) did not differ between the group that had undergone a sham operation and the group that had undergone resection. Concentration-response curves to the muscarinic agonist bethanechol had similar values for the estimated concentration at which the response is half-maximal (EC50) and maximal active stress in both groups. However, significant increases were observed in the frequency and amplitude of spontaneous and bethanechol-stimulated phasic contractions of jejunal tissues obtained from resected rats. The presence of tetrodotoxin (10(-6) mol/L) did not alter the active contractile response (tonic stress, phasic frequency and amplitude) of resected tissues. Thus, after massive intestinal resection, longitudinal smooth muscle shows no adaptive change with respect to basal or active stress but does exhibit an increase in phasic contractile activity. This altered response is non-neural; it may reflect changes in the smooth muscle itself or, alternatively, modulation of myogenic activity by prejunctional effects or by the activity of the interstitial cells of Cajal.

Hyperplasia of the muscularis propria in response to massive intestinal resection in rat.

Adaptation of the muscularis propria to intestinal resection is not well studied. Growing, 150- to 200-g Sprague-Dawley rats were divided into a resected group (R), which had 75% of the jejunoileum removed; a sham-resected group (SR); and a group of untreated controls (C). Food intake and weight gain were documented. Animals were killed on days 0, 10, 20, 30, or 40 (n = 14 animals for each day in each group). Small-intestinal length and jejunal circumference, wet weight/cm, thickness of the muscle layers, muscle morphometry, mg protein, and micrograms DNA per cm of the muscularis propria were measured. R rats had an initially greater food intake than SR or C animals, but the rate of weight gain was not different between groups. There was no significant increase in length of the residual intestine in R animals during the postoperative adaptive period, but circumference was significantly increased in R compared with SR or C animals. Wet weight/cm, mg protein, and micrograms DNA per cm of the muscularis propria were significantly greater in R compared with SR or C animals, but there was no change in thickness of the smooth-muscle layers in R versus SR or C rats. The number of cross-sectioned circular smooth-muscle cells/mm2 and the ratio of mg protein/micrograms DNA/cm length of muscularis propria were not different in R compared with SR or C animals. Intestinal resection resulted in a significant increase in circumference but not length of the residual intestine. A significant increase in the mass/cm, with no change in the number of cross-sectioned circular smooth-muscle cells/mm2 or in mg protein/micrograms DNA/cm of the muscularis propria, indicates that the adaptive response of muscularis propria is characterized by hyperplasia. This response potentially confers benefit to the organ and animal as a whole as a mechanism that permits structural and functional adaptation of the muscularis propria to resection.

Massive intestinal resection depresses circular smooth muscle contractility in the rat.

To determine whether functional changes in in vitro contractility and in vivo gastrointestinal transit accompany the adaptive structural changes seen in jejunal circular muscle after massive intestinal resection, rats were subjected to either surgical resection of 75% of the mid-jejunoileum or a sham operation. Basal stress in response to stretch was similar for both groups on postoperative days 10, 20, 30, and 40. By day 10 after surgery, tissues from resected rats exhibited a significant reduction in bethanechol-stimulated tonic stress and in frequency of phasic contractions. The amplitude of spontaneous phasic activity was significantly increased; however, following cholinergic stimulation, the magnitude of the increase in the amplitude of phasic activity was significantly reduced. Experiments with tetrodotoxin (10(-6) M) indicated a myogenic origin to the reduction in bethanechol-stimulated tonic stress and the reduced frequency and altered amplitude of phasic contractile activity in resected animals. The tonic stress developed in response to depolarization with KCl did not differ significantly between sham-operated and resected rats. Transit studies showed no change in the rate of gastric emptying after resection but did reveal a significant reduction in the velocity of intestinal transit. Thus, following massive intestinal resection the bethanechol-stimulated tonic stress response and phasic contractile activity of circular smooth muscle are significantly reduced, concomitant with altered intestinal transit. The reduction in contractility in the resected animals may be due to an alteration at the level of the smooth muscle receptor and (or) its signal transduction pathway.

Prostaglandins inhibit inflammatory mediator release from rat mast cells.

BACKGROUND: Mast cells have been implicated in the pathogenesis of gastric ulceration. It is possible that prostaglandins exert cytoprotective effects by inhibiting the release of proulcerogenic mediators from mast cells. METHODS: The effects of three prostaglandins on the release of platelet-activating factor, tumor necrosis factor, and histamine from rat mast cells (peritoneal and intestinal mucosal) activated with calcium ionophore or antigen were assessed. RESULTS: Upon stimulation with either agonist, intestinal mucosal and peritoneal mast cells released significant quantities of platelet-activating factor. Preincubation for 5 minutes with misoprostol, prostaglandin (PG)E2, 16,16-dimethyl PGE2, ketotifen, or PF-5901 concentration-dependently reduced ionophore-stimulated platelet-activating factor release; significant effects were observed with picomolar to nanomolar concentrations of the prostaglandins and micromolar concentrations of the other compounds. Tumor necrosis factor release from peritoneal and mucosal mast cells was also significantly inhibited by the prostaglandins in picomolar to nanomolar concentrations. Misoprostol and PGE2 at concentrations of 5-50 nmol/L significantly inhibited histamine release from peritoneal mast cells stimulated with ionophore but did not affect histamine release stimulated by antigen. CONCLUSIONS: These results show potent inhibitory effects of prostaglandins on the release of pro-ulcerogenic inflammatory mediators from mast cells. Such effects may contribute to the protective and anti-inflammatory effects of prostaglandins in the gastrointestinal tract and elsewhere.

Diabetic Chinese hamsters: metabolic effects of long term guar gum consumption.

The effect of 13 weeks of guar gum or cellulose diet consumption upon metabolic parameters was examined in diabetic and control adult Chinese hamsters. Diabetic hamsters displayed typical diabetic metabolic profiles. Both 8% guar gum and 8% cellulose diets maintained body weights in all 4 groups during the study. Diabetic and control hamsters fed guar gum drank less water as the study progressed. At weeks 9 and 13, diabetic hamsters fed guar gum excreted less urine compared to those fed cellulose. Diabetic hamsters fed guar gum had reduced urinary glucose excretion at weeks 1, 9 and 13 compared to those fed cellulose. Control hamsters fed either diet had normal urine volumes with only traces of glucose. Similar fasting plasma glucose levels were measured initially for all diabetic hamsters; all 3 subsequent measurements revealed lower levels for the group fed guar gum. Control hamsters had normal fasting plasma glucose levels. Comparable fasting plasma insulin levels were measured for all diabetic hamsters; these levels increased during the study. Control hamster fasting plasma insulin levels were 3 times higher and did not change. Throughout the study, diabetic hamsters fed guar gum consistently had healthier metabolic profiles than those fed cellulose.

Guar gum consumption in adolescent and adult rats: short- and long-term metabolic effects.

Metabolic responses to short- and long-term guar gum consumption were studied in adolescent and adult rats. For the long-term study, male adolescent rats were divided into four groups (n = 60/group) and fed guar gum, cellulose, or bran diet for 67 weeks. Metabolic studies (food--water intake, feces--urine output, body weight, carbohydrate tolerance) were performed eight times during the 67 weeks. The guar gum group consumed less diet throughout the entire study and gained less weight over the first 20 weeks compared with the cellulose and bran groups. A second bran-fed group was food restricted over the first 20 weeks to match the reduced weight gain of the guar gum group and then fed ad libitum. Reduced plasma glucose excursions were measured for only the guar gum group after both fibre-free glucose and sucrose challenges at weeks 6, 12, and 18; from 24 to 64 weeks all four groups had similar glucose tolerance responses. Twenty-four hour urinary glucose excretion was similar during all eight metabolic studies up to 64 weeks for guar gum and cellulose groups. In the short-term study, male adolescent (200 g; n = 10/group) and adult (630 g; n = 15/group) rats were divided into five and four groups, respectively, and fed guar gum, guar by-product (GBP), cellulose, or bran diet for 6 weeks. A metabolic study was performed during the 6th week. Adolescent rats fed guar gum or GBP diets gained less weight than the cellulose group; only the guar gum group displayed improved carbohydrate tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin biosynthesis by gastric mucosa. I. Studies in rat.

A technique for determination of the prostaglandin E2 biosynthetic capacity ( PGBC ) of gastric mucosa is described. The effects of food deprivation and indomethacin pretreatment on PGBC were studied. Indomethacin (1 mg/kg i.p.) significantly reduced the PGBC of fundal and antral tissue. This effect was more marked in the fundal tissue. Food deprivation for up to 22 h had no effect on fundal PGBC . In the antrum, a 12-hour fast caused a significant reduction in PGBC while a 22-hour fast had no effect. These changes in PGBC may relate to the increase in susceptibility to gastric ulceration caused by fasting or indomethacin pretreatment. This technique may be applicable to clinical studies.