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CYCLO‐OXYGENASE‐1 INHIBITION INCREASES ACID SECRETION BY MODULATING H + ,K + ‐ATPase EXPRESSION AND ACTIVATION IN RABBIT PARIETAL CELLS
Author(s) -
Nandi Jyotirmoy,
Das Pratap K,
Zinkievich J Michael,
Baltodano Juan D,
Levine Robert A
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05032.x
Subject(s) - histamine , parietal cell , medicine , gastric acid , prostaglandin , endocrinology , chemistry , basal (medicine) , gastric mucosa , prostaglandin e2 , secretion , atpase , stomach , biology , biochemistry , enzyme , insulin
SUMMARY1 In the present study, we evaluated the role of cyclo‐oxygenase (COX)‐1 and COX‐2 on gastric acid secretion in rabbit isolated parietal cells and gastric glands by examining [ 14 C]‐aminopyrine uptake, prostaglandin (PG) E 2 synthesis and COX‐1, COX‐2 and proton pump expression at baseline and after treatment with various concentrations of specific COX‐1 (SC‐560), COX‐2 (5,5‐dimethyl‐3‐(3‐fluorophenyl)‐4‐(4‐methyl‐sulphonyl)phenyl‐2 (5H)‐furanone; DFU) and non‐specific COX (indomethacin) inhibitors. 2 In parietal cells, SC‐560 and indomethacin, over the concentration range 10 −8 to 10 −4 mol/L, dose‐dependently increased basal and 10 −4 mol/L histamine‐stimulated aminopyrine uptake and inhibited PGE 2 synthesis, whereas DFU (10 −8 to 10 −5 mol/L) had no effect. However, at 10 −4 mol/L, DFU augmented histamine‐stimulated aminopyrine uptake by 135% and inhibited PGE 2 synthesis by 39%, indicating an inhibition of COX‐1 at this higher concentration. 3 The SC‐560‐, DFU‐ and indomethacin‐induced augmentation of histamine‐stimulated aminopyrine uptake was reduced to basal levels after 10 −5 mol/L lansoprazole treatment in parietal cells and gastric glands, whereas 10 −4 mol/L ranitidine only partially inhibited such augmentation. 4 Only COX‐1 was detected in parietal cells. However, both COX‐1 and COX‐2 were expressed in gastric glands, with relative protein density of COX‐1 being sixfold higher than that of COX‐2. Protein levels of COX‐1 in parietal cells and those of COX‐1 and COX‐2 in gastric glands remained unchanged, regardless of inhibitor treatment, either alone or with histamine. 5 Parietal cell proton pump expression was significantly enhanced by 10 −5 mol/L SC‐560 and 10 −4 mol/L indomethacin (by 29 and 31%, respectively) and pump activity was enhanced by 61 and 65%, respectively. In contrast, 10 −5 mol/L DFU had no effect. 6 In conclusion, the data indicate that inhibition of COX‐1‐ but not COX‐2‐derived PGE 2 synthesis is involved in augmentation of non‐steroidal anti‐inflammatory drug‐induced gastric acid secretion in parietal cells by enhancing expression and activation of the proton pump.