A possible role of protein kinase C in augmenting H+ secretion by nonsteroidal anti-inflammatory drugs

J Nandi, J Crockett and RA Levine

Department of Medicine, State University of New York Health Science Center, Syracuse.

The effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on H+ secretion 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), enhanced histamine- and dibutyryl adenosine 3',5'-cyclic monophosphate- stimulated H+ secretion by 20 to 34%. Similarly, a protein kinase C (PKC) inhibitor, 1-(5-isoquinolinesulfonyl)- 2-methyl piperazine (H7, 5 x 10(-5) M), and a calcium ionophore, A23187 (10(-6) M) augmented basal and the aforementioned secretagogue-stimulated H+ secretion by approximately 50% and 20%, respectively, but a PKC activator, phorbol ester (12-O-tetradecanoyl phorbol 13-acetate, 10(-7)-10(-6) M), had no effect. The augmentation of H+ secretion by these agents was blocked by a calcium antagonist, lanthanum chloride (5 x 10(-4) M). In rabbit PC, H7 augmented secretagogue-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% without affecting dibutyryl adenosine 3',5'-cyclic monophosphate-stimulated H+ secretion. Furthermore, NSAIDs and H7- induced augmentation of dibutyryl cyclic adenosine monophosphate- stimulated H+ secretion was prevented by 12-O-tetradecanoyl phorbol 13- acetate (10(-7)-10(-6) M) in frog gastric mucosa and rabbit PC. Unlike H7, NSAIDs had no direct inhibiting action on PC membrane or cytosolic fractions of PKC, but they inhibited Sn-1,2-diacylglycerol level in PC by 20 to 30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 269, Issue 3, pp. 932-940, 06/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics