Differential inhibition of platelet thromboxane and lung prostacyclin production by sulphinpyrazone, acetylsalicylic acid and indomethacin by human tissues in vitro.
To compare the inhibition of human platelet and lung cyclo-oxygenases by sulphinpyrazone (SP), acetylsalicylic acid (ASA) and indomethacin, we investigated their effects on platelet thromboxane A2 (TxA2) production during spontaneous clotting and on prostacyclin (PGI2) and TxA2 productions of superfused minced human lung. The synthesis of proaggregatory, vasoconstricting TxA2 and antiaggregatory, vasodilating PGI2 were evaluated by measuring the concentration of their stable metabolites thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha respectively, by radioimmunoassays. The basal platelet TxB2 production was 241.0 +/- 56.3 ng/ml (mean +/- SEM, n = 12). The concentrations needed for 50% inhibition of this production (IC50) were 41.3 mumol/l for sulphinpyrazone, 6.3 mumol/1 for ASA and 0.094 mumol/l for indomethacin. The lung generated 23.8 +/- 5.5 ng/g/min (mean +/- SEM, n = 6) of 6-keto-PGF1 alpha and 8.5 +/- 1.8 ng/g/min of TxB2. The IC50 values for pulmonary 6-keto-PGF1 alpha and TxB2 productions were 530.0 mumol/l for SP, 370.0 mumol/l for ASA and 50.0 mumol/l for indomethacin. Thus pulmonary cyclo-oxygenase, presumably originating from endothelial cells, was 13, 59, and 532 times more resistant to these prostaglandin synthesis inhibitors (PGI's) than platelet cyclo-oxygenase. These data suggest that there are considerable differences in the concentration ranges of various PGI's by which the PGI2/TxA2 balance can be shifted to a dominance of PGI2.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D013442:Sulfinpyrazone / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000096:biosynthesis
D016861:Cyclooxygenase Inhibitors; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D001241:Aspirin; D013442:Sulfinpyrazone; D007213:Indomethacin