Interaction of the non-steroidal anti-inflammatory drug flufenamic acid with gastric acid secretion and H+/K(+)-ATPase.
1. The effects of the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid on H+ production in isolated and enriched guinea-pig parietal cells and on H+/K(+)-ATPase activity in ion-tight inside-out membrane vesicles from pig gastric mucosa were studied. 2. At low concentrations (0.1 and 1.0 mumol/L), flufenamic acid increased the secretory response of parietal cells to dibutyryl cyclic AMP (dbcAMP). At higher concentrations (10 and 100 mumol/L) it progressively inhibited basal and dbcAMP-stimulated acid production. 3. Flufenamic acid (10 mumol/L) increased K+ (0.5-10.0 mmol/L) and K+ (0.5-1.0 mmol/L) plus gramicidin-stimulated ATPase activity in gastric membrane vesicles. The Km value for K+ (1.6 and 1.0 mmol/L in the absence and presence of gramicidin, respectively) was decreased to 0.8 and 0.5 mmol/L, respectively. At higher concentrations (greater than or equal to 50 mumol/L), flufenamic acid inhibited K+ plus gramicidin-stimulated ATPase activity (inhibited concentration at 50% [IC50] = 186 mumol/L) and reduced the proton concentration (IC50 = 50 mumol/L). 4. It is concluded that flufenamic acid-induced enhancement of dibutyryl cyclic AMP-stimulated H+ production in the parietal cell reflects the stimulation of H+/K(+)-ATPase. We suggest that activation of the enzyme involves increased affinity of K+ towards the K(+)-binding site of the enzyme and/or increased KCl permeability at the vesicle membrane. The inhibitory action of the drug on H+ production in parietal cells results from a detergent and/or protonophoric-like action at the apical parietal cell membrane, and from inhibition of H+/K(+)-ATPase activity.
Beil
W
W
Institut für Allgemeine Pharmakologie, Medizinische Hochschule Hannover, Germany.
Greite
C
C
Sewing
K F
KF
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D005439:Flufenamic Acid / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D006168:Guinea Pigs; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011522:Protons
D011522:Protons; D005439:Flufenamic Acid; D003994:Bucladesine; D011189:Potassium Chloride; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase