Reduced thromboxane receptor affinity and vasoconstrictor responses in placentae from diabetic pregnancies.

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 44,000 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 alpha, respectively. Incorporation of [14C]-arachidonic acid into both thromboxane B2 and 6-keto-prostaglandin F1 alpha 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.