Differential inhibition of fetal vascular prostacyclin and platelet thromboxane synthesis by nonsteroidal anti-inflammatory drugs in humans.
To study the synthesis of proaggregatory, vasoconstricting thromboxane A2 (TxA2) by human fetal platelets we evaluated the formation of its stable metabolite thromboxane B2 (TxB2) during thrombin-induced spontaneous clotting of blood from the umbilical vein of 13 healthy infants. We further compared the effects of acetylsalicylic acid, indomethacin, naproxen sodium and diclofenac sodium on platelet TxA2 production in response to thrombin-induced aggregation during spontaneous clotting, and on prostacyclin (PGI2) production by umbilical arteries in a superfusion system by measuring the 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) concentration in the superfusate. For every drug four concentrations covering the clinically significant range were studied. The basal production of TxB2 by fetal platelets (181.5 +/- 22.5 ng/ml, mean +/- SEM) was comparable with that of adults (216.1 +/- 11.5 ng/ml). The concentrations of the drugs needed for 50% inhibition of TxB2 generation were 19.0 mumol/l for acetyl-salicylic acid, 0.09 mumol/l for indomethacin, 0.06 mumol/l for diclofenac sodium and 4.2 mumol/l for naproxen sodium. The basal production of 6-keto-PGF1 alpha by umbilical arteries was 24.5 +/- 3.2 ng/min/g. The concentrations of the drugs needed for 50% inhibition of 6-keto-PGF1 alpha production were 360.0 mumol/l for acetylsalicylic acid, 4.0 mumol/l for indomethacin, 2.3 mumol/l for diclofenac sodium and 15.0 mumol/l for naproxen sodium. Thus fetal platelet cyclo-oxygenase was 4-44 times more sensitive to these prostaglandin synthesis inhibitors than umbilical artery cyclo-oxygenase.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D011247:Pregnancy; D011453:Prostaglandins / Q000096:biosynthesis*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013931:Thromboxanes / Q000096:biosynthesis*
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D013931:Thromboxanes; D013928:Thromboxane A2; D011464:Epoprostenol