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.
Fondacaro
J D
JD
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania.
Kolpak
D C
DC
Burnham
D B
DB
McCafferty
G P
GP
D000818:Animals; D000930:Antidiarrheals / Q000627:therapeutic use*; D002217:Carbachol / Q000494:pharmacology; D002432:Cecum / Q000187:drug effects / Q000502:physiology* / Q000601:surgery; D002746:Chlorpromazine / Q000494:pharmacology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000633:toxicity; D003000:Clonidine / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D007419:Intestinal Secretions / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000930:Antidiarrheals; D011459:Prostaglandins E, Synthetic; C017244:16,16-dimethylprostaglandin E; D009020:Morphine; D002217:Carbachol; D002772:Cholera Toxin; D003000:Clonidine; D002746:Chlorpromazine