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Indomethacin potentiates acetylcholine‐induced vasodilation by increasing free radical production
Author(s) -
De Angelis Antonella,
Rinaldi Barbara,
Capuano Annalisa,
Rossi Francesco,
Filippelli Amelia
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705877
Subject(s) - acetylcholine , cromakalim , chemistry , vasodilation , nitric oxide , medicine , sodium nitroprusside , superoxide , hydroxocobalamin , endocrinology , aorta , thoracic aorta , vascular smooth muscle , pharmacology , biochemistry , agonist , receptor , organic chemistry , smooth muscle , cyanocobalamin , vitamin b12 , enzyme
We studied the effects of indomethacin on endothelium‐dependent and ‐independent vascular relaxation in rat thoracic aortic rings and its role in superoxide anion (O 2 − ) production. We measured isometric force changes in response to acetylcholine (Ach, 1 n M –0.1 m M ), sodium nitroprusside (SNP, 0.1 n M –0.1 μ M ; a nitric oxide (NO) donor) and cromakalim (1 n M –0.1 m M ; a K ATP ‐channel opener) in aorta rings contracted with norepinephrine (NE, 0.1 μ M ). Indomethacin (10 μ M ; 20 min) significantly increased Ach‐induced vasodilation (EC 50 decreased from 8.99 μ M to 16 n M ). The free radical scavengers superoxide dismutase and 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐ N ‐oxyl completely reverted these effects. Indomethacin did not affect SNP‐ or cromakalim‐induced vasodilation. Neither acetylsalicylic acid (ASA, 5–100 μ M ; 15 min) nor ketoprofen (1−100 μ M ; 15 min) affected Ach, SNP and cromakalim concentration–response curves. Incubation of the aorta with Ach (1 μ M ) rapidly and markedly increased intracellular NO fluorescence in the aorta endothelium. Indomethacin did not affect Ach‐induced NO production. We measured intracellular O 2 − in the aorta endothelium with dihydroethidium (DHE) dye. Indomethacin significantly increased O 2 − fluorescence versus controls. Neither ASA nor ketoprofen affected O 2 − fluorescence. Nitrotyrosine staining was increased in indomethacin‐treated aorta sections exposed to Ach, which indicates endogenous formation of peroxynitrite. It was low in aorta sections exposed to Ach alone or with ASA or ketoprofen. We cannot judge if indomethacin‐induced endothelium‐dependent vasodilation damages or protects the cardiovascular system. Here, we show that indomethacin acts on the cardiovascular system regardless of cyclooxygenase inhibition.British Journal of Pharmacology (2004) 142 , 1233–1240. doi: 10.1038/sj.bjp.0705877