Recent findings on the mode of action of laxatives: the role of platelet activating factor and nitric oxide.

Platelet activating factor (PAF) is a phospholipid mediator of inflammation and stimulates anion secretion in animals and in isolated preparations of human colon. Nitric oxide (NO), synthesized from the amino acid L-arginine, is an important enteric inhibitory neurotransmitter. In addition, NO-donating compounds stimulate anion secretion in rat and guinea-pig colon.

The osmotic and intrinsic mechanisms of the pharmacological laxative action of oral high doses of magnesium sulphate. Importance of the release of digestive polypeptides and nitric oxide.

A common use for high doses of oral magnesium salts is to produce a laxative effect to treat constipation. In the intestinal lumen the poorly absorbable magnesium ions (and other ions such as sulphate) exert an osmotic effect and cause water to be retained in the intestinal lumen. This increases the fluidity of the intraluminal contents and results in a laxative action.

Relationship between nitric oxide and platelet-activating factor in castor-oil induced mucosal injury in the rat duodenum.

The modulation of platelet activating factor (PAF) formation in duodenal tissue by nitric oxide (NO) released in response to castor oil was studied in rats pretreated with NG-nitro-L-arginine methyl ester (L-NAME, 6.25-25 mg/kg, i.p.

NG-nitro-L-arginine methyl ester reduces senna- and cascara-induced diarrhoea and fluid secretion in the rat.

Senna (60 mg/kg orally) and cascara (800 mg/kg orally)-induced diarrhoea and net fluid secretion were studied in rats for a time period of 1-8 h. NG-Nitro-L-arginine methyl ester (L-NAME) (2.5-25 mg/kg i.

Eicosanoids and histamine mediate C5a-induced electrolyte secretion in guinea pig ileal mucosa.

C5a is a biologically active polypeptide formed during the course of complement activation and is known to possess histamine-releasing and neutrophil chemotactic properties. In the present study, we have demonstrated that C5a can regulate electrolyte transport across guinea pig ileum, and we have investigated its mechanism of action. Segments of ileum stripped of longitudinal muscle were mounted in Ussing chambers (Krebs' buffer, 37 degrees C, 95% O2/5% CO2) for monitoring short-circuit current (Isc).

Preferential binding of the novel prostaglandin SC-46275 to canine gastric versus intestinal receptors.

Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity.

Bradykinin acting on B2 receptors contracts colon circular muscle cells by IP3 generation and adenylate cyclase inhibition.

Receptor subtypes and intracellular signaling events involved in bradykinin-evoked contraction of colonic circular muscle are unknown. We studied the roles of inositol trisphosphate (IP3) and cyclic AMP generation and the selectivity for B1 and B2 receptors in guinea pig colon. Bradykinin induced concentration-dependent contraction of circular muscle strips with an EC50 of 2 x 10(-8) M that was inhibited by the B2 antagonist D-Argo-(Hyp3,Thi5,8,D-Phe7)-bradykinin but not the B1 antagonist des-Arg9-[Leu8]bradykinin.

Colitis reduces short-circuit current response to inflammatory mediators in rat colonic mucosa.

Inflammatory mediators may contribute to the diarrhea associated with colitis. Although the secretory action of such mediators is reported in normal tissue, there is little information regarding their effects on inflamed tissue. We examined the short-circuit current response (Isc) to these mediators, in mitomycin-C (MC)-induced colitis, a model with histological similarities to colitis in man.

Dissociation of castor oil-induced diarrhoea and intestinal mucosal injury in rat: effect of NG-nitro-L-arginine methyl ester.

1. Castor oil (2 ml orally) produced diarrhoea in rats 1-7 h after challenge, which was associated with gross damage to the duodenal and jejunal mucosa. 2.

Nitric oxide involvement in sodium choleate-induced fluid secretion and diarrhoea in rats.

Bile salt-induced diarrhoea, net water and electrolyte secretion, gastrointestinal transit and nitric oxide (NO) synthase activity were studied in rats. NG-Nitro-L-arginine methyl ester (2.5-25 mg/kg i.

Nitric oxide as a mediator of the laxative action of magnesium sulphate.

1. Magnesium sulphate was studied for its effects on diarrhoea, fluid secretion, gastrointestinal transit and nitric oxide (NO) synthase activity in rats. 2.

Nitric oxide as a mediator of bisacodyl and phenolphthalein laxative action: induction of nitric oxide synthase.

Bisacodyl and phenolphthalein are diphenylmethane laxatives that have effects on intestinal water and electrolyte transport and smooth muscle contractility. Nitric oxide (NO) is produced in the intestine, where it stimulates electrolyte secretion and relaxes smooth muscle. Therefore, we studied in rats the effect of these laxatives on diarrhea, fluid transport in vivo, gastrointestinal transit and NO synthase activity in the absence and presence of inhibitors of NO synthesis.

Clinical relevance of basic research in peptic ulcer disease.

Historically, the interplay between basic research and clinical observation has been essential in the development of new therapies for peptic ulcer disease. That histamine is an important regulator of acid secretion emerged from basic research, followed by the clinical development and use of the H2-receptor antagonists. Basic research contributed again by defining the importance of H+/K(+)-ATPase in acid secretion, resulting in a new class of useful antisecretory agents.

Stereospecific actions of misoprostol on rat colonic electrolyte transport.

Misoprostol (Miso) produces a mild, transient diarrhea in some patients, which is believed to be partly due to intraluminal fluid accumulation. To better understand this diarrheagenic action, we compared the effects of Miso, its 4 stereoisomers (11R16R, 11R16S, 11S16S, 11S16R), misoprostol free acid (Miso-FA), and 16,16-dimethyl PGE2 (dmPGE2) on rat colonic electrolyte transport in vitro. Increases in short-circuit current (Isc) were measured (after serosal addition) in segments of mucosa stripped of muscularis and mounted in Ussing chambers.

Effect of the thiol-oxidizing agent diamide on NH2Cl-induced rat colonic electrolyte secretion.

The granulocyte-derived oxidant, monochloramine (NH2Cl), is known to stimulate chloride ion secretion in rat distal colonic mucosa mounted in Ussing chambers, through mechanisms that are sensitive and insensitive to tetrodotoxin (TTX). The possible role of intracellular thiols, in the mechanism of action of NH2Cl as a secretagogue, was evaluated with the thiol-oxidizing agent diamide and by measuring tissue sulfhydryl levels in response to NH2Cl. Serosal exposure to the antioxidant glutathione (0.

Direct evidence for nitric oxide stimulation of electrolyte secretion in the rat colon.

Nitric Oxide (NO) is synthesized in the intestinal tract and may serve as a physiological regulator of intestinal ion transport and/or a pathophysiologic mediator of secretory diarrhea associated with inflammatory mucosal diseases. Indirect approaches, employing inhibitors of nitric oxide synthase or compounds capable of donating NO in solution, have been used to demonstrate the effects on gastrointestinal muscle and the mucosa. To determine directly whether nitric oxide itself is capable of stimulating electrolyte secretion we mounted muscle-stripped rat distal colon in Ussing chambers and monitored short-circuit current (Isc), as an indicator of effects on mucosal ion transport.

Oxidant-evoked release of acetylcholine from enteric neurons of the rat colon.

In the presence of halides, granulocytes generate hypochlorous acid and, subsequently, chlorinated amines (chloramines). These lipophilic, potent reactive oxygen metabolites may contribute to the mucosal pathophysiology associated with inflammatory bowel disease. A common symptom of inflammatory bowel disease is mucosal secretion of fluid and electrolytes, leading to diarrhea.

Mitomycin C-induced colitis in rats: a new animal model of acute colonic inflammation implicating reactive oxygen species.

The mechanism of the tissue damage induced by colonic inflammation in ulcerative colitis is not established. We therefore developed and characterized a simple new rat model of acute colonic inflammation induced by a single systemic injection of mitomycin C. After an intraperitoneal injection of mitomycin-C, colon histologic examination revealed transient (3 to 14 days) diffuse, colonic inflammation and injury that, like human ulcerative colitis, was limited to the mucosal layer.

Effects of SC-41930 on leukocyte adherence and emigration in rat mesenteric venules.

This study demonstrates that SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-p ropyl-2H-1-benzopyran-2-carboxylic acid, an orally active LTB4 receptor antagonist, reduces LTB4-induced leukocyte adhesion and emigration in rat mesenteric venules. The mesentery of Sprague-Dawley rats was prepared for intravital microscopic examination and venules of 25-35 microns were chosen for evaluation. In control animals, LTB4 (20 nM) was superfused over the mesentery for 30 min.

Endothelin-1 stimulates contraction and ion transport in the rat colon: different mechanisms of action.

Endothelin-like immunoreactivity has been detected in all regions of the rat gastrointestinal tract. In the present study, we studied the effect of endothelin-1 (ET-1) on muscle contraction and ion transport in the rat colon. Isometric tension was recorded in colonic muscle strips oriented along their longitudinal axis.

Indomethacin-induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products.

Although the pathogenetic mechanisms underlying indomethacin-induced mucosal injury remain undefined, the results from recent studies suggest that leukocyte adherence in gastric microvessels may be an important component of this injury process. The objective of this study was to determine whether clinically relevant plasma concentrations of indomethacin promote leukocyte-endothelial cell adhesive interactions in postcapillary venules. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 s) and emigrated leukocytes were measured in rat mesenteric venules.

Effect of colonic inflammation on mucin inhibition of Escherichia coli RDEC-1 binding in vitro.

Intestinal mucus protects the underlying epithelium against adhesion and invasion by microbial pathogens and their products. In inflamed colonic mucosa there are both histochemical and biochemical changes in the major organic constituent of mucus, goblet cell-derived mucin. To determine if these changes result in differences in functional properties of mucin, inhibition of adherence of piliated Escherichia coli, strain RDEC-1 (serotype O15:H-), by mucin purified from distal colons of normal rabbits was compared with inhibition by mucin from colons of rabbits with dinitrochlorobenzene-induced colitis.

Effect of endothelin-1 on guinea pig gallbladder smooth muscle in vitro.

The purpose of this study was to investigate the pharmacological activity of endothelin-1 (ET-1) on guinea pig gallbladder smooth muscle. Guinea pig gallbladder muscle strips were mounted in 10-ml siliconized organ baths containing Krebs' solution. After 1 hr of equilibration, ET-1 was added cumulatively.