A POSSIBLE ROLE OF PROTEIN-KINASE-C IN AUGMENTING H+ SECRETION BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on H+ sec retion were studied in frog gastric mucosa and rabbit parietal cells ( PC). In frog gastric mucosa, aspirin (10(-5) M) and ibuprofen (10(-4) M), but not indomethacin, naproxen and carprofen (10(-4) M each), enha nced histamine- and dibutyryl adenosine 3',5'-cyclic monophosphate-sti mulated H+ secretion by 20 to 34%. Similarly, a protein kinase C (PKC) inhibitor, 1-(5-isoquino-linesulfonyl)-2-methyl piperazine (H-7, 5 X 10(-5) M) and a calcium ionophore, A23187 (10(-6) M) augmented basal a nd the aforementioned secretagog-stimulated H+ secretion by approximat ely 50% and 20%, respectively, but a PKC activator, phorbol ester (12- O-tetradecanoyl phorbol 13-acetate, 10(-7)-10(-6) M), had no effect. T he augmentation of H+ secretion by these agents was blocked by a calci um antagonist, lanthanum chloride (5 x 10(-4) M). In rabbit PC, H-7 au gmented secretagog-stimulated H+ secretion by 60 to 150%, whereas 12-O -tetradecanoyl phorbol 13-acetate (10(-7) M) inhibited carbachol- and histamine-stimulated H+ secretion, respectively, by 65% and 52% withou t affecting dibutyryl adenosine 3',5'-cyclic monophosphate-stimulated H+ secretion. Furthermore, NSAIDs and H-7-induced augmentation of dibu tyryl cyclic adenosine monophosphate-stimulated H+ secretion was preve nted by 12-O-tetradecanoyl phorbol 13-acetate (10(-7)-10(-6) M) in fro g gastric mucosa and rabbit PC. Unlike H-7, NSAIDs had no direct inhib iting action on PC membrane or cytosolic fractions of PKC, but they in hibited Sn-1,2-diacytglycerol level in PC by 20 to 30%. The data indic ate that NSAIDs-induced augmentation of secretagog-stimulated H+ secre tion may be mediated by indirect regulation of PKC.