15-hydroxy-5-8-11-13-eicosatetraenoic-acid and flosulide

Selective cyclooxygenase (COX)-2 inhibitors are expected to cause fewer gastric side effects because of sparing of COX-1-dependent prostaglandin (PG) synthesis in the gastric mucosa. However, the possible contribution of COX-2 to overall gastric PG biosynthesis is not known. This study demonstrates constitutive expression of COX-2 mRNA and protein in apparently healthy human and rabbit gastric mucosa. This basal expression of COX-2 protein in human gastric mucosa was increased by lipopolysaccharide and phorbol ester, indicating its up-regulation in response to appropriate stimuli. The functional significance of COX-2-dependent PG formation was studied in terms of PGE2 generation in the rabbit mucosa and its inhibition by the COX-2-selective inhibitor flosulide. There was concentration-dependent (IC50 = 107 +/- 55 nM) and ultimately complete inhibition of PGE2 generation by flosulide. In addition, gastric mucosa generated 15-hydroxyeicosatetraenoic acid upon treatment with acetylsalicylic acid. The data suggest an important role for COX-2-dependent PG production in apparently healthy gastric mucosa and raise the issue of whether selective COX-2 inhibitors might also interfere with physiological PG formation and actions in the stomach.

Topics: Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Enzyme Induction; Fibroblasts; Gastric Mucosa; Humans; Hydroxyeicosatetraenoic Acids; Indans; Isoenzymes; Lipopolysaccharides; Membrane Proteins; Muscle, Smooth; Prostaglandin-Endoperoxide Synthases; Rabbits; RNA, Messenger