Pathogenic importance of pepsin in ischemia/reperfusion-induced gastric injury.
We investigated the role of pepsin in the development of ischemia/reperfusion (I/R)-induced gastric lesions in rats. Under urethane anesthesia, the pylorus was ligated, the celiac artery was clamped, and 1 ml of HCl (50-150 mM) was instilled in the stomach. Then, reperfusion was established 15 min later by removing the clamp, and 2 h later the stomach was assessed for gross mucosal damage. Pepstatin (a specific pepsin inhibitor) or pepsin was given i.g. after the pylorus was ligated while cimetidine, omeprazole, or atropine was given s.c. 30 min before the ligation. I/R produced hemorrhagic gastric injury, with a concomitant increase in the amount of pepsin secreted, and the degree of both these responses was dependent on the concentration of HCl. The formation of lesions by IR in the presence of 100 mM HCl was significantly prevented by atropine or bilateral vagotomy, but neither omeprazole nor cimetidine had any effect. Intragastric administration of pepstatin dose-dependently reduced the severity of the I/R-induced gastric lesions, the effect being significant even at 0.1 mg/kg, while that of pepsin markedly aggravated these lesions. The increased pepsin output during I/R was associated with luminal acid loss and significantly inhibited by bilateral vagotomy or pretreatment with atropine but not cimetidine or omeprazole, while pepstatin significantly inhibited the pepsin activity. In conclusion, we suggest that pepsin plays a pivotal role in the pathogenesis of I/R-induced gastric lesions, and pepsin secretion is increased during I/R, the process being associated with acid back-diffusion and mediated through a vagal-cholinergic pathway.
Kotani
Tohru
T
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical Universitym Misasagi, Yamashina, Kyoto 607-8414, Japan.
Murashima
Yukiko
Y
Kobata
Atsushi
A
Amagase
Kikuko
K
Takeuchi
Koji
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology; D010434:Pepsin A / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010436:Pepstatins / Q000008:administration & dosage / Q000494:pharmacology; D011708:Pylorus / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
D000897:Anti-Ulcer Agents; D010436:Pepstatins; D001285:Atropine; D002927:Cimetidine; D010434:Pepsin A; D009853:Omeprazole; C031375:pepstatin