Effects of hypoxia and indomethacin on fetal release of leukotrienes and thromboxane by the perfused human placental cotyledon

Abstract

Thromboxane has been implicated in the pathogenesis of maternal hypertension in high-risk pregnancies, but potential abnormalities in thromboxane-mediated constriction of fetoplacental vessels has not been examined. Using the isolated perfused fetoplacental cotyledon, we compared the vasoconstrictor responses to a thromboxane mimetic, U46619, in placentae from normal women and women with diabetes mellitus (classes C, D and R). Increases in perfusion pressure in response to bolus injections of U46619 were used to construct dose-response curves. The threshold dose of U46619 to cause a pressor response was similar in placentae from normal and diabetic pregnancies, but the slope of the dose-response curve was decreased by 39 per cent in placentae from diabetic pregnancies compared with normal controls (P <0.01). To examine the potential contribution of altered thromboxane receptors, equilibrium binding studies were performed using the thromboxane antagonist [3H]-SQ29548 to a 44000 g fraction of placental homogenate. The affinity of thromboxane receptors was significantly decreased in placentae from diabetic pregnancies compared with normal controls [Kd=41.9±7.9 (n=6) versus control, 21.4±1.3 nm (n=26), P<0.001]. In contrast, the density of thromboxane receptor sites was not significantly changed (diabetes, 176.0±6.2 versus control, 150.3±6.5 fmol/mg, P=not significant). Placental production of thromboxane and prostacyclin were measured by the incorporation of [14C]-arachidonic acid into [14C]-thromboxane B2 and [14C]-6-keto-prostaglandin F1∞, respectively. Incorporation of [14C]-arachidonic acid into both thromboxane B2 and 6-keto-prostaglandin F1α was similar in placentae from diabetic and normal pregnancies. We conclude that vascular responsiveness to thromboxane is reduced in placentae from mothers with diabetes by a receptor-mediated mechanism. These changes may contribute to abnormalities in the regulation of fetoplacental haemodynamics, growth and development in pregnancies complicated by diabetes mellitus.