Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors

• Published in: The American journal of physiology Vol. 263; no. 4 Pt 1; pp. E718 - E723
• Main Authors: Wilkes, B M, Hollander, A M, Sung, S Y, Mento, P F
• Format: Journal Article
• Language: English
• Published: United States 01-10-1992
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arteries - drug effects; Cyclooxygenase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; Meclofenamic Acid - pharmacology; Placenta - blood supply; Prostaglandin Endoperoxides, Synthetic - pharmacology; Receptors, Thromboxane - antagonists & inhibitors; Thromboxanes - antagonists & inhibitors; Thromboxanes - pharmacology
• ISSN: 0002-9513
• DOI: 10.1152/ajpendo.1992.263.4.e718

The effects of 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 x 10(-5) M) significantly blunted the pressor response to U-46619, but not to angiotensin II, and inhibited thromboxane B2 formation in placental slices (IC50, 4.80 x 10(-8) 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 IC50 of 2.61 x 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 (IC50, 3.27 x 10(-4) M). However, aspirin at a dose of 2.0 x 10(-3) M did not inhibit [3H]SQ 29548 binding. The data indicate that some cyclooxygenase inhibitors blunt thromboxane actions by interfering with binding at 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.