REDUCED THROMBOXANE RECEPTOR AFFINITY AND VASOCONSTRICTOR RESPONSES IN PLACENTAE FROM DIABETIC PREGNANCIES

Thromboxane has been implicated in the pathogenesis of maternal hypert ension in high-risk pregnancies, but potential abnormalities in thromb oxane-mediated constriction of fetoplacental vessels has not been exam ined. Using the isolated perfused fetoplacental cotyledon, we compared the vasoconstrictor responses to a thromboxane mimetic, U46619, in pl acentae from normal women and women with diabetes mellitus (classes C, D and R). Increases in perfusion pressure in response to bolus inject ions of U46619 mere used to construct dose-response curves. The thresh old dose of U46619 to cause a presser response was similar in placenta e from normal and diabetic pregnancies, but the slope of the dose-resp onse curve was decreased by 39 per cent in placentae from diabetic pre gnancies compared with normal controls (P < 0.01). To examine the pote ntial contribution of altered thromboxane receptors, equilibrium bindi ng studies mere performed using the thromboxane antagonist [H-3]-SQ295 48 to a 44000 g fraction of placental homogenate. The affinity of thro mboxane receptors was significantly decreased in placentae from diabet ic pregnancies compared with normal controls [K-d = 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 chang ed (diabetes, 176.0 +/- 6.2 versus control, 150.3 +/- 6.5 fmol/mg, P = not significant). Placental production of thromboxane and prostacycli n were measured by the incorporation of [C-14]-arachidonic acid into [ C-14]-thromboxane B-2 and [C-14]-6-keto-prostaglandin F-1 alpha, respe ctively. Incorporation of [C-14]-arachidonic acid into both thromboxan e B-2 and 6-keto-prostaglandin F-1 alpha, was similar in placentaefrom diabetic and normal pregnancies. We conclude that vascular responsive ness to thromboxane is reduced in placentae from mothers with diabetes by a receptor-mediated mechanism. These changes may contribute to abn ormalities in the regulation of fetoplacental haemodynamics, growth an d development in pregnancies complicated by diabetes mellitus.