AJP - Endocrinology and Metabolism, Vol 263, Issue 4 E718-E723, Copyright © 1992 by American Physiological Society
Cyclooxygenase inhibitors blunt thromboxane action in human placental arteries by blocking thromboxane receptors
B. M. Wilkes, A. M. Hollander, S. Y. Sung and P. F. Mento
Department of Medicine, North Shore University Hospital, Manhasset, New York 11030.
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.
