Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat

Abstract

Cholecystokinin is a gastrointestinal hormone known to physiologically regulate pancreatic protein secretion and gallbladder contractility. Some evidence suggests that cholecystokinin is also involved in the maintenance of gastrointestinal mucosal integrity. This study was undertaken to ascertain whether cholecystokinin could prevent the gastric mucosal injury induced by acidified ethanol and what role prostaglandins, and type A and type B cholecystokinin receptors might play in this process. Conscious, fasted rats were given subcutaneous saline or cholecystokinin octapeptide (10-100 micrograms/kg) 30 min before a 1-ml oral gastric bolus of acidified ethanol (150 mM HCl/50% ethanol). Five minutes later, rats were sacrificed and the total area of macroscopic injury quantitated (square millimeters). In additional experiments using a similar protocol, 1 ml of either the cyclooxygenase inhibitor, indomethacin (5 mg/kg), a type A cholecystokinin receptor antagonist, L-364,718 (0.01-1 mg/kg), or the type B cholecystokinin receptor antagonist, L-365,260 (12.5-25 mg/kg) was given intraperitoneally 30 min prior to pretreatment with cholecystokinin octapeptide. Cholecystokinin octapeptide dose-dependently prevented mucosal injury from acidified ethanol (corroborated by histology). The protective effect of cholecystokinin octapeptide was completely negated by L-364,718 and partially reversed by indomethacin, while L-365,260 had no discernible effect in this process. In a further study, cholecystokinin was unable to prevent the damaging effects of aspirin and the inhibition of endogenous prostaglandins. This, it appears that cholecystokinin is able to maintain mucosal integrity in the face of a damaging insult by activation of type A cholecystokinin receptors, an effect mediated, at least in part, through the release of endogenous prostaglandins.

Role of Bombesin and Cholecystokinin Receptors in Gastric Injury Induced by Hemorrhagic Shock in the Rat

“…Similar protective actions of exogenous gastrin and CCK have also been reported in earlier studies performed in alcohol-induced gastric injury models [13][14][15]. These studies have shown that the gastroprotective action of the gastrin was mainly mediated by mucosal defense mechanisms whereas that of CCK was mainly mediated by endogenous prostaglandins.…”

“…It has been already reported that bombesin prevents macroscopic gastric injury caused by 96% ethanol given orogastrically to conscious rats [33]. Bombesin maintained the integrity of the gastric epithelium by decreasing the depth of the damage caused by the irritant [14]. In the saline-treated rats, acidified ethanol caused severe necrosis of the gastric epithelium down to the submucosa.…”

“…Bombesin was given subcutaneously in doses of 10, 50 or 100 Ìg/kg, while the control group received saline/1% BSA solution. This range of doses was chosen due to earlier reports about the prevention of gastric injury induced by alcohol in conscious rats [13][14][15]. Thirty minutes after each pretreatment, hemorrhagic shock was induced as described below.…”

“…Finally, as a control, both MK-329 and L-365,260 was given in the same experimentally designed group. Again, the doses were given based on the earlier reports [13][14][15].…”

“…Moreover, these two peptides have already been shown to have potent gastroprotective activity when given exogenously [12,13]. In the stomach, the protective actions of both gastrin and CCK are inhibited by administration of type B and type A CCK receptor antagonists, respectively, in alcohol-induced gastric injury in rats [13,14].…”