Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors
Wilkes, B.M.; Hollander, A.M.; Sung, S.Y.; Mento, P.F.
American Journal of Physiology 263(4 Pt 1): E718-E723
1992
ISSN/ISBN: 0002-9513 PMID: 1415690 Document Number: 392616
The effects cyclooxygenase inhibitors on thromboxane-mediated vasoconstriction in human placental arteries were studied in the isolated perfused fetoplacental cotyledon. The stable thromboxane agonist U-46619 caused a dose-related increase in perfusion pressure in the fetal side of the cotyledon. Meclofenamate (3.3 times 10-15 M) significantly blunted the pressor response to U-46619, but not to angiotensin II, and inhibited thromboxane B-2 formation in placental slices (IC-50, 4.80 times 10-1 M). The mechanism by which meclofenamate prevented thromboxane-induced vasoconstriction was studied using ligand-binding techniques in a membrane fraction prepared from placental cotyledons. Meclofenamate caused a dose-related inhibition of binding of the thromboxane receptor antagonist (3H)SQ 29548 with an IC-50 of 2.61 times 10-5 M. Scatchard analysis of equilibrium binding demonstrated that meclofenamate reduced the number of binding sites without altering the affinity of the receptor, suggesting a noncompetitive mechanism. Indomethacin also caused a dose-related inhibition of thromboxane binding (IC-50, 3.27 times 0-4 M). However, aspirin at a dose of 2.0 times 10-3 M did not inhibit (3H)SQ 29548 binding. The data indicate that some cyclooxygenase inhibitors blunt thromboxane actions by interfering with binding a thromboxane receptor sites. These studies identify a new mechanism by which cyclooxygenase inhibition by some nonsteroidal anti-inflammatory drugs can prevent thromboxane action in fetoplacental blood vessels in vitro independent of reductions in thromboxane formation.