Effects of cyclooxygenase inhibitors on ex vivo cysteinyl-leukotriene production by whole human blood allowed to clot spontaneously. Comparison to stimulated blood.
In ex vivo experiments we have investigated the effects of single oral administrations of aspirin (100 or 1000 mg) or ibuprofen (200 or 1200 mg) on the formation of immunoreactive thromboxane (TX) B2 and cysteinyl-leukotrienes (LT) by whole human blood in vitro. Whole human blood was allowed to clot spontaneously and in addition, in the presence of the chemotactic tripeptide f-Met-Leu-Phe (FMLP, 1 microM), or the non-physiological ionophore A 23187 (10 microM). Oral pretreatment with aspirin or ibuprofen led to dose-dependent inhibition of the TXB2 production in the presence of any of the stimuli used. After drug pretreatment the cysteinyl-LT production was not significantly enhanced in blood stimulated with FMLP or allowed to clot spontaneously as compared to values prior to oral drug administration. However, pronounced inhibition of the cyclooxygenase pathway was accompanied by an enhanced cysteinyl-LT formation when ionophore A 23187 was used as a stimulus. This could also be shown in experiments where the cyclooxygenase inhibitors were added in vitro. The higher oral dose of aspirin reduced the ex vivo cysteinyl-LT production in spontaneously clotting blood. By reverse phase HPLC immunoreactive cysteinyl-LT were characterized as a mixture of LTD4 and LTE4 as well as small amounts of LTC4. The data show that in the presence of therapeutic cyclooxygenase inhibitors no enhanced formation of cysteinyl-LT occurs in human blood in vitro after physiological stimuli such as contact activation of the clotting cascade or FMLP.
Weide
I
I
Department of Pharmacology and Toxicology, Ruhr-University, Bochum, Germany.
Tschorn
K
K
Simmet
T
T
D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis*
D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D016718:Arachidonic Acid; D000001:Calcimycin; D013929:Thromboxane B2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D001094:Arachidonate 5-Lipoxygenase; D001241:Aspirin; D007052:Ibuprofen