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At least 181 records · Page 10Linked to original sources
PubMed1989

Novel calmodulin antagonist CGS 9343B inhibits secretory diarrhea.

The goal of this study was to determine whether secretory diarrhea could be ameliorated by pharmacological alteration of the second messenger systems which mediate intestinal fluid and electrolyte transport. Calmodulin is an important intermediate in the mucosal signal-transduction pathways that regulate intestinal NaCl transport. We tested a selective inhibitor of calmodulin, CGS 9343B, for antidiarrheal activity in two different models of secretory diarrhea. Diarrhea was induced in mice by p.o. administration of castor oil (0.6 ml) and in rats by i.p. injection of PGE2 (150 micrograms). We compared the antidiarrheal effects of CGS 9343B to other prototype antidiarrheal agents including morphine, loperamide and chlorpromazine in the castor oil-induced model of secretory diarrhea in mice. CGS 9343B was the most potent of these agents, eliminating diarrhea in 100% of mice at a dose of 1 mg/kg (p.o.). Morphine, loperamide and chlorpromazine were 3 to 10 times weaker than CGS 9343B. In this model, we measured changes in the amount of feces eliminated (grams) and loss of body weight (grams) as indicators of the rate of intestinal propulsion, based on the assumption that reduced fecal passage and concomitantly smaller weight loss represented reduced propulsion of intestinal contents, or constipation. Although the other agents caused equal degrees of constipation and antidiarrheal activity, CGS 9343B did not exert any significant antipropulsive effects at antidiarrheal doses in castor oil-treated mice. To further differentiate these agents on the basis of antipropulsive activity, we compared them for effects on the rate of transit of a p.o. administered radioactive marker in normal mice (noncastor oil-treated).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1988

Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum.

BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.

Animals↗
PubMed1990

Cecectomized rat. A model of experimental secretory diarrhea in conscious animals.

Evaluation of antisecretory antidiarrheal agents in animal models is limited primarily to extrapolations of efficacy from enteropooling studies in vivo, isolated intestinal loops in situ, and Ussing flux chamber preparations in vitro. While these standard techniques are useful, they do not mimic secretory diarrhea. Our studies indicate that in rats, the cecum may serve a "reservoir" function in response to secretagogue administration. Thus, diarrhea is not observed consistently and reliably in this species to allow valid evaluation of potential antidiarrheal agents. Therefore, we have developed a reproducible model of secretory diarrhea utilizing conscious cecectomized rats by surgical resection of the cecum, without compromising ileocecal patency, and by the use of potent intestinal secretagogues. Animals quickly recover and maintain normal growth and other physiologic parameters for as long as 60 days. After 48 hr on standard chow, secretory diarrhea can be induced by oral administration of standard intestinal secretagogues (dimethyl prostaglandin E2, cholera toxin, or carbachol). Dimethyl prostaglandin E2 (300 micrograms/kg, p.o.) induces diarrhea within 1 hr that continues for approximately 3.5 hr. Oral administration of known antidiarrheal agents chlorpromazine (10 mg/kg), clonidine (1 mg/kg), or morphine (10 mg/kg) all significantly reduce fecal output within 30-60 min following administration. These studies indicate that in the rat, the cecum may serve as a fluid reservoir during periods of small intestinal hypersecretion and that the cecectomized rat serves as a useful, accurate, and reliable tool for evaluating new compounds with proposed antidiarrheal activity.

Animals↗