16-16-dimethylprostaglandin-e2 and Diarrhea

The amelioration of secretory diarrhea has been reported after the administration of zaldaride maleate (ZAL), a selective calmodulin inhibitor, to male rodents. In this study, the antidiarrheal effect of ZAL in female rats was compared with that in male rats. In female and male rats, ZAL significantly ameliorated 16,16-dimethyl prostaglandin E2-induced diarrhea at doses of 1 and 3 mg/kg (p.o.), respectively, with ID50 values of 0.7 mg/kg (p.o.) in the females and 10.3 mg/kg (p.o.) in males. In castor oil-induced diarrhea, ZAL also significantly reduced the incidence of diarrhea in female and male rats at doses of 10 and 30 mg/kg (p.o.), respectively. When the same dose of ZAL was given orally to female and male rats, the maximum plasma level of this compound was approximately 3 times higher in female rats than in male rats. In contrast, after intravenous administration of the same dose of ZAL to female and male rats, the total clearance of this compound was similar. In an Ussing chamber experiment, the inhibitory action of ZAL on vasoactive intestinal polypeptide-induced ion secretion in the colon showed no difference between female and male rats. In conclusion, the antidiarrheal effect of ZAL in female rats is more potent than that in males, and could be due to the difference in plasma levels of this compound between female and male rats after oral administration.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antidiarrheals; Benzimidazoles; Castor Oil; Colon; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Sprague-Dawley; Secretory Rate; Sex Characteristics

The antidiarrheal action of zaldaride maleate (ZAL) after oral, intravenous and subcutaneous administration was examined to determine whether ZAL acts systemically or locally in the intestine of rats. Oral administration of ZAL inhibited castor oil- and 16,16-dimethyl prostaglandin E2-induced diarrhea; however, intravenous or subcutaneous administration of ZAL was ineffective. When ZAL was orally administered, the area under the plasma concentration time curve of the compound was lower than that of ZAL following intravenous or subcutaneous administration at the maximum doses studied. The antidiarrheal effect of ZAL was not dependent on its plasma concentration level. These results suggest that ZAL acts locally in the intestinal tract in rats.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Animals; Antidiarrheals; Area Under Curve; Benzimidazoles; Castor Oil; Cathartics; Diarrhea; Injections, Intravenous; Injections, Subcutaneous; Male; Rats; Rats, Sprague-Dawley

Myoelectric recordings of the opossum gastrointestinal tract were performed during continuous infusion of 16,16-dimethyl prostaglandin E2 at 0.1, 1, 2 and 5 micrograms/kg X h. Continuous administration of prostaglandin caused a dose-dependent reduction of the duration of the migrating myoelectric complex cycle and an increase in the velocity of phase III migration from the duodenum to the terminal ileum. The reduction of the migrating myoelectric complex cycle was due to a shortening of the duration of both phase I and II. Bolus administration of 16,16-dimethyl prostaglandin E2 caused intense spike activity for 2-4 min in all recording sites simultaneously. Administration of indomethacin did not change the myoelectric activity of the gastrointestinal tract. Infusion of prostaglandin E2 caused diarrhoea in eight of forty experiments. These changes in gastrointestinal motility may be important contributory factors in the pathogenesis of prostaglandin-induced diarrhoea.

Topics: 16,16-Dimethylprostaglandin E2; Action Potentials; Animals; Diarrhea; Digestive System Physiological Phenomena; Female; Gastrointestinal Motility; Indomethacin; Male; Muscle, Smooth; Opossums; Prostaglandins E, Synthetic; Sphincter of Oddi; Time Factors

Rats treated with subcutaneous 16,16-dimethyl prostaglandin E2 (16,16-dimethyl PGE2, 100 micrograms kg-1) exhibited diarrhoea even when their ileo-caecal junctions were tied, thereby eliminating contributions from small intestinal transit or fluid accumulation (enteropooling). The origin of the watery stool appeared to be the caecum, since tying the caecal-colonic junction eliminated it. The acceleration of colonic transit is likely to be a primary mechanism of PGE2-induced diarrhoea in the rat, since both normal animals and those with tied ileo-caecal junctions exhibited almost the same incidence of diarrhoea. Subcutaneous prostacyclin (PGI2) (2 mg kg-1 every 60 min) suppressed 16,16-dimethyl PGE2-induced diarrhoea in normal rats and in those with tied ileo-caecal junctions. Colonic transit measured in rats with cannula preimplanted in their proximal colon indicated that 16,16-dimethyl PGE2 enhanced colonic transit and PGI2 suppressed this increase. Thus, PGI2 can inhibit diarrhoea in the rat caused by 16,16-dimethyl PGE2 by suppressing colonic transit exclusive of its effects on small intestinal transit and enteropooling.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Colon; Diarrhea; Epoprostenol; Gastrointestinal Motility; Male; Prostaglandins; Rats

M&B 28,767 [(+/-)11-deoxy-16-phenoxy-omega-tetranor PGE1] and 16, 16'-dimethyl PGE2 methylester (DMPG) were compared for their effects on gastric acid secretion (GAS) and gastric ulceration (GU), employing various laboratory models. In anaesthetised rats, GAS was stimulated by a continuous i.v. infusion of pentagastrin (30 micrograms/kg/h), and PG analogues were perfused through the stomach for 1 h. M&B 28,767 (3-15 micrograms/kg/h) and DMPG (3-60 micrograms/kg/h) reduced GAS in a dose-related manner, the ED50 values being 4 and 15 micrograms/kg/h respectively. In conscious rats possessing indwelling gastric cannulae, oral doses of M&B 28,767 (0.025-0.1 microgram/kg) and DMPG (0.50-1.0 microgram/kg) caused a prolonged inhibition of pentagastrin-stimulated GAS. M&B 28,767 was 17 times more potent than DMPG; the respective ED50 values were 0.036 and 0.6 microgram/kg. Indomethacin-induced ulceration in rats, was reduced by both M&B 28,767 and DMPG; the respective ED50 values being 3.0 and 0.8 micrograms/kg. Both compounds given orally increased gastrointestinal motility in mice; M&B 28,767 (1-3 mg/kg) and DMPG (0.1-0.3 mg/kg) caused diarrhoea, the former being about 0.1 times as potent as the latter. In another test, M&B 28,767 (0.5-5.0 mg/kg) and DMPG (10-40 micrograms/kg) overcame morphine-induced constipation in a dose-related manner, the respective ED50s being 0.9-1.4 mg/kg and 20-40 micrograms/kg. Thus, M&B 28,767 had a better profile of activity than DMPG as an antisecretory and antiulcer agent.

Topics: 16,16-Dimethylprostaglandin E2; Alprostadil; Animals; Constipation; Diarrhea; Gastric Acid; Gastrointestinal Motility; Indomethacin; Male; Mice; Morphine; Pentagastrin; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Stomach Ulcer

Several neuroleptics known to bind to calmodulin were tested for anti-diarrheal activity and were compared with the opiate anti-diarrheals loperamide and diphenoxylate. All inhibited the intestinal fluid secretion induced by 16,16-dimethyl prostaglandin E2 and castor oil-induced diarrhea in rats as a function of dose, the order of potency being loperamide approximately equal to diphenoxylate greater than chlorpromazine greater than promethazine greater than amitriptyline. The opiates loperamide and diphenoxylate were found to compete with [3H]trifluoperazine binding to calmodulin in the presence of calcium. These opiates were approximately 3 times more potent inhibitors of [3H]trifluoperazine binding than chlorpromazine. A positive correlation between calmodulin binding and anti-diarrheal activity was demonstrated.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antidiarrheals; Antipsychotic Agents; Body Fluids; Calcium-Binding Proteins; Calmodulin; Castor Oil; Diarrhea; Diphenoxylate; Female; Intestinal Mucosa; Loperamide; Protein Binding; Rats; Rats, Inbred Strains

Ulcerative colitis is distinguished by abundant prostaglandin E2 (PGE 2) in the stools and by severe diarrhea. To determine whether luminal PGE2 alters normal colonic absorption, NA+ and Cl-transport across isolated rat proximal colon were studied before and after 16,16 dimethyl PGE2 (dmPGE2) addition to flux chambers. Luminal administration of dmPGE2 significantly reduced the net mucosal to serosal fluxes of Na+ and Cl-. These antiabsorptive tive effects of dmPGE2 on NA+ and Cl- active transport were reflected by a reduced metabolic rate of colonic tissue slices incubated with dmPGE2. Addition of dmPGE2 significantly reduces oxidation of glucose by the colon. Structurally, dmPGE2 reduced the length of colonic mucosal microvilli, thereby decreasing absorptive surface area. These results suggest that PGE2 released into the colonic lumen of patients with ulcerative colitis exerts antiabsorptive effects on the colon and in this way contributes to the associated diarrhea.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Biological Transport, Active; Chlorides; Colitis, Ulcerative; Colon; Diarrhea; Intestinal Absorption; Male; Prostaglandins E, Synthetic; Rats; Sodium

A series of PGE2, 16,16-dimethyl-PGE2, and PGF2 alpha analogues modified at the carboxyl terminus with tetrazole, amide, acylurea, imide, and sulfonimide functionalities was evaluated for uterine stimulant, bronchodilator, hypotensive, gastric antisecretory, and diarrheal activity. These compounds were prepared by modification of the Corey prostaglandin synthesis utilizing as a key step condensation of known hemiacetals with the ylide derived from the requisite substituted phosphonium salts. Structure--activity relationships suggest that a proton at the C-1 position appears necessary for agonist activity and the acidity of this proton has a relatively greater influence on activity than pendant steric bulk. Noteworthy are the tissue-selective bronchodilator activity of N-acetyl-PGE2-carboxamide and the selectivity for uterine tissue of N-methanesulfonyl-PGE2-carboxamide, 2-decarboxy-2-(tetrazol-5-yl)-16,16-dimethyl-PGE2, N-acetyl-16,16-dimethyl-PGE2-carboxamide, and N-methanesulfonyl-16,16-dimethyl-PGE2-carboxamide.

Topics: Animals; Blood Pressure; Bronchodilator Agents; Diarrhea; Dogs; Female; Gastric Juice; Guinea Pigs; In Vitro Techniques; Male; Mice; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Rats; Structure-Activity Relationship; Uterine Contraction