New method of inducing intestinal lesions in rats by intraduodenal administration of aspirin.
OBJECTIVE
Enteroscopic observation has clearly demonstrated that non-steroidal anti-inflammatory drugs/low-dose aspirin (usually enteric-coated) induces hemorrhagic lesions, including ulcers and bleeding, in the small intestine of patients at a high incidence. Such intestinal lesions induced by NSAIDs have been confirmed in animal experiments. With aspirin, however, it has long been believed that it is difficult to induce any damage in the intestinal mucosa of laboratory animals. Therefore, we established a new method of inducing intestinal hemorrhagic lesions in rats by injecting aspirin into the proximal duodenum.


METHODS
Under ether anesthesia, aspirin (50-200 mg/body), suspended in 2% methylcellulose (with or without 0.1 N HCl), was injected into the proximal duodenum of normally fed or 20-h non-fed rats (male Sprague-Dawley, 9 weeks old). At 1 h after treatment, the animals were killed with ether and the entire small intestine was removed for histological examination. In some experiments, 1% Evans blue was injected (i.v.) into the rats 1 h after aspirin treatment to visualize the lesions. An image analyzer determined the total area of the intestinal lesions. Oral proton pump inhibitors and histamine H(2)-receptor blockers were given 1 h before aspirin injection. 16,16-dimethyl prostaglandin E(2) (dmPGE(2)) was given s.c. 30 min before aspirin injection.


RESULTS
Aspirin alone clearly induced severe lesions (including bleeding and ulcers) mainly in the jejunum at 100% incidence. Total score of lesions per rat obtained by histological examination was similar to the damaged area quantified with the dye method. Dose-related induction of lesions by aspirin was confirmed both by the histological and dye methods. The irritable effect of aspirin suspended in 0.1 N HCl solution was the same as that of aspirin alone; 0.1 N HCl alone induced only minor lesions in the intestine. Both proton pump inhibitors and histamine H(2)-receptor blockers, at doses that inhibit gastric acid secretion, had no or little effect on aspirin-induced intestinal lesions. Pretreatment with dmPGE(2) (3, 10, 30 microg/kg) showed significant prevention of both aspirin- and HCl/aspirin-induced intestinal lesions.


CONCLUSIONS
This new aspirin lesion model will be useful for screening defensive drugs against aspirin-induced intestinal lesions and to elucidate the underlying mechanism.
Nonoyama
Kenichi
K
Department of Pharmacology, School of Pharmacy, Doshisha Women's College, Kyoto, Japan.
Nakagawa
Kanako
K
Amagase
Kikuko
K
Takeuchi
Koji
K
Nakamura
Masahiko
M
Okabe
Susumu
S
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004381:Duodenal Ulcer / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D004386:Duodenum / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007267:Injections; D007413:Intestinal Mucosa / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008855:Microscopy, Electron, Scanning; D010438:Peptic Ulcer Hemorrhage / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors; D015064:16,16-Dimethylprostaglandin E2; D001241:Aspirin