Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors.
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.
Wilkes
B M
BM
Department of Medicine, North Shore University Hospital, Manhasset, New York 11030.
Hollander
A M
AM
Sung
S Y
SY
Mento
P F
PF
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001158:Arteries / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008469:Meclofenamic Acid / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013931:Thromboxanes; D008469:Meclofenamic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid