Cellular mechanisms of beta-carotene-induced gastric cytoprotection in indomethacin-treated rats.

Indomethacin (IND) is a non-steroidal anti-inflammatory agent which is widely used in the treatment of various inflammatory disorders. The drug causes gastrointestinal injury in humans and experimental animals. The aim of these studies was to examine the time course correlation between the macroscopic appearance of mucosal damage, tissue level of PGE(2) and adenosine nucleotide metabolism during the development of indomethacin (IND)-induced mucosal damage and its prevention by beta-carotene.The observations were carried out on both sexes of CFY-strain rats, weighing 180-200 g. Gastric mucosal damage was produced by subcutaneous administration of IND (20 mg/kg). beta-Carotene (Hoffman-La Roche, Switzerland) was given intragastrically at the time of IND administration at doses of 0.01, 0.1, 1 and 10 mg/kg. The animals were sacrificed at 0, 1, 2, 3 and 4 h after IND administration when the number and severity of mucosal lesions were noted and the tissue levels of ATP, ADP, AMP, cAMP, lactate and PGE(2) were measured from the total homogenate of gastric mucosa. The ratio of ADP/ATP, the values of the adenylate pool (ATP+ADP+AMP), and 'energy charge' [(ATP+0.5ADP)/(ATP+ADP+AMP)] were calculated.It was found that: (a) gastric mucosal lesions appear macroscopically 2 h after IND administration; (b) the tissue level of ATP decreased, while ADP was increased 1 h after administration; (c) the most significant decrease in cAMP was found 1 h after IND administration, and thereafter its level returned to baseline; (d) beta-carotene dose-dependently prevented the IND-induced mucosal damage and elevated the cAMP level, but it did not alter the mucosal PGE(2) level 3 or 4 h after IND administration; (e) beta-carotene produced an elevation in ATP and a decrease in ADP level; (f) no significant changes were found in 'energy charge' of the gastric mucosa in IND-treated animals.The development of gastric mucosal damage due to IND was associated with increased energy liberation, i.e. transformation of ATP into ADP, and decreased ATP-cAMP transformation. The significant decrease in cAMP preceded the macroscopic appearance of mucosal damage. The increase in ATP-cAMP transformation is involved in the development of beta-carotene-induced gastric cytoprotection.