Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of
pepsin in the pathogenesis of
reflux esophagitis has not been well studied. In the present study, we examined the effect of
pepstatin, a specific inhibitor of
pepsin, on
acid reflux esophagitis.
Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr.
Pepstatin,
ecabet Na (the anti-
ulcer drug), and
L-glutamine were administered intragastrically after the
ligation.
Pepstatin or
ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal
acid secretion in pylorus-ligated rats.
Pepstatin significantly inhibited
pepsin activity in vivo and in vitro, while
ecabet Na inhibited this activity in vitro. By contrast,
L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of
L-glutamine the development of esophageal lesions was totally prevented by coadministration of
pepstatin or
ecabet Na.
L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of
pepsin in vitro. In addition, intragastric administration of exogenous
pepsin worsened the severity of esophageal damage. These results suggest that
pepstatin is highly effective against
acid reflux esophagitis, without influencing
acid secretion, while
L-glutamine aggravated these lesions by increasing the
pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that
pepsin plays a major pathogenic role in the development of
acid reflux esophagitis.