A possible role of protein kinase C in augmenting H+ secretion by nonsteroidal anti-inflammatory drugs.
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)
Department of Medicine, State University of New York Health Science Center, Syracuse.
J
J
Nandi
J
J
Crockett
R A
RA
Levine
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011522:Protons; D011817:Rabbits; D011892:Rana catesbeiana; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007546:Isoquinolines; D010879:Piperazines; D011522:Protons; D003994:Bucladesine; D006632:Histamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin; D007052:Ibuprofen