Study on paradoxical effects of NSAIDs on platelet activation.
We recently described a stimulatory effect of high doses (> 100 mumol/L) diclofenac on platelet adhesion. In this study we extend our research to the possible biochemical mechanisms of the observed effects, to other non steroidal anti-inflammatory drugs (NSAIDs) (flurbiprofen, indomethacin, acetylsalicylic acid, ibuprofen, nitrofenac and nitroflurbiprofen) and to the effect of high doses diclofenac and flurbiprofen on platelet aggregation. We observed that high doses of diclofenac and of flurbiprofen, but not of the other tested NSAIDs, increased platelet adhesion at doses ranging from 100 to 500 mumol/L, an effect completely removed by the 12-lipoxygenase-inhibitor nordihydroguaiaretic acid. Moreover, they had no pro-aggregating effect, inhibiting platelet aggregation induced by 10 mumol/L arachidonic acid and dose-dependently increasing the [Ca2+]i. Finally, whereas no basal nitric oxide release by washed platelets was detected, when platelets were incubated by 500 mumol/L diclofenac or flurbiprofen, the production of nitric oxide, as measured by amounts of nitrite released, was 4.4 +/- 0.5 and 3.8 +/- 0.4 pmol/5 x 10(8) platelets/min, respectively. Our data indicate that high doses diclofenac and flurbiprofen are promoters of the early phases of platelet activation, probably through the 12-lipoxygenase pathway.
Andrioli
G
G
Institute of Clinical Chemistry, University of Verona, Italy.
Lussignoli
S
S
Gaino
S
S
Benoni
G
G
Bellavite
P
P
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001092:Arachidonate 12-Lipoxygenase / Q000097:blood; D034341:Aristolochic Acids; D002118:Calcium / Q000097:blood; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009637:Masoprocol / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D010616:Phenanthrenes / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D034341:Aristolochic Acids; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010616:Phenanthrenes; D004008:Diclofenac; D009569:Nitric Oxide; D005480:Flurbiprofen; D009637:Masoprocol; C000228:aristolochic acid I; D001092:Arachidonate 12-Lipoxygenase; D010741:Phospholipases A; D002118:Calcium