Prostaglandin-independent inhibition of calcium transport by nonsteroidal anti-inflammatory drugs: differential effects of carboxylic acids and piroxicam.
Nonsteroidal antiinflammatory drugs (NSAID) alter calcium fluxes in several tissues. The present study was designed to assess simultaneously the effects of NSAID on ATP-dependent 45Ca accumulation into rat and hamster liver mitochondria, microsomes and plasma membrane vesicles and prostaglandin (PG) and thromboxane synthesis in these organelles. The carboxylic acid NSAID, indomethacin, meclofenamate and naproxen inhibited 45Ca accumulation by mitochondria and microsomes while plasma membrane 45Ca transport was not inhibited. Similarly, none of the NSAID inhibited 45Ca transport by human erythrocyte ghosts. Addition of exogenous PGE2, PGH2 or a thromboxane mimetic [U46619 [(15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid] ) did not reverse the inhibition by NSAID. ID50 values for inhibition of 45Ca uptake into mitochondria and microsomes were identical, 25 to 30 microM for meclofenamate and 80 to 90 microM for indomethacin. The ID50 values for inhibition of PGE synthesis were less than 1 microM for meclofenamate and 4 to 5 microM for indomethacin. Dose-response relationships for inhibition of 45Ca uptake were identical with controls in mitochondria isolated from normal or essential fatty acid-deficient Long-Evans rats even though PGE synthesis in essential fatty acid-deficient was only 20% of that in normal rats. In contrast to the other NSAID tested, piroxicam, a member of a new class of NSAID, the oxicams, did not affect mitochondrial or microsomal 45Ca transport at concentrations up to 300 microM, while the ID50 for inhibition of PGE synthesis was 0.35 microM. The mechanism for inhibition of 45C transport by NSAID is not known but does not appear to be related to inhibition of fatty acid cyclooxygenase.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002264:Carboxylic Acids / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D008469:Meclofenamic Acid / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D009288:Naproxen / Q000494:pharmacology; D010894:Piroxicam; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D013843:Thiazines / Q000494:pharmacology*; D013931:Thromboxanes / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D016861:Cyclooxygenase Inhibitors; D007473:Ion Channels; D011453:Prostaglandins; D013843:Thiazines; D013931:Thromboxanes; D010894:Piroxicam; D008469:Meclofenamic Acid; D009288:Naproxen; D002118:Calcium; D007213:Indomethacin