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The effects of feeding with gamma-linolenic acid (GLA) in comparison with linoleic acid on aspirin-induced gastric hemorrhage were studied in the rat. Gastric damage was examined macroscopically and histologically. Intragastric administration of 100 mg aspirin daily for 4 weeks produced hemorrhage in 3 of 8 rats receiving a linoleic-acid-enriched diet, but none in 8 rats receiving GLA-enriched diet. The levels of linoleic acid in plasma and liver phospholipids were significantly increased, whereas those of arachidonic acid (AA) were reduced in plasma and liver phospholipids of aspirin-treated animals fed linoleic acid. Similar, more pronounced changes occurred in those animals with hemorrhage. The reduced ratios of arachidonate/linoleate suggest that fatty acid desaturation in these animals was depressed. Treatment with GLA prevented these changes. Our results demonstrated that GLA could protect the gastric mucosa from aspirin-induced damage by bypassing the depressed delta-6-desaturation and thus providing a precursor for the synthesis of AA and prostaglandins.