Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.
The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.
Shimizu
I
I
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
Kawashima
K
K
Yoshida
N
N
Ito
T
T
D015064:16,16-Dimethylprostaglandin E2 / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D002368:Castor Oil / Q000008:administration & dosage / Q000633:toxicity; D002432:Cecum / Q000601:surgery; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D003967:Diarrhea / Q000139:chemically induced* / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005772:Gastrointestinal Transit / Q000187:drug effects; D007279:Injections, Subcutaneous; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D007977:Levallorphan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008139:Loperamide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D007977:Levallorphan; C045482:N-methyllevallorphan; D008139:Loperamide; D009020:Morphine; D002368:Castor Oil; D015064:16,16-Dimethylprostaglandin E2