Effect of anti-inflammatory analgesic drugs on the regulation of cytosolic pH by anion antiport.
Four nonsteroidal anti-inflammatory analgesic drugs acetylsalicylic acid (aspirin), salicylic acid, indomethacin and piroxicam were tested for their action on chloride/bicarbonate exchange by anion antiport and on the regulation of cytosolic pH (pHi) in Vero cells. The Na+-independent Cl-/HCO3- exchange regulates pHi back to normal after alkalinization and is therefore in a state of high activity at alkaline pHi, whereas it is in a state of low activity when pHi is below neutrality. Preincubation with the drugs at low pH strongly increased the activity of the Na+-independent Cl-/HCO3- exchange, whereas at high pH the antiport was inhibited. The Na+-dependent Cl-/HCO3- exchange, which is most active at low pHi and normalize pHi after acidification, was inhibited after preincubation with the drugs. In cells that had been incubated with the drugs, pHi was 0.1 to 0.4 pH units lower than in cells that had been incubated in the absence of drugs. The prostaglandins E2, F2 and I2 had little effect on anion antiport, and did not counteract the effects of the anti-inflammatory drugs on Cl-/HCO3- exchange, indicating that these actions of the drugs are not due to the inhibition of prostaglandin synthesis. The relevance of our findings to the clinical effects of these drugs is discussed.
Tønnessen
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Institute for Cancer Research, Norwegian Radium Hospital, Montebello, Oslo.
Aas
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Sandvig
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Olsnes
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D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D012964:Sodium / Q000378:metabolism; D014709:Vero Cells
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001639:Bicarbonates; D002712:Chlorides; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D012964:Sodium; D015232:Dinoprostone; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid