Peroxide induces vasoconstriction in the human placenta by stimulating thromboxane

Abstract

Placental lipid peroxides and thromboxane are abnormally increased in preeclampsia. Thromboxane is a potent vasoconstrictor of the placental vasculature. Peroxides stimulate cyclooxygenase (prostaglandin H synthase), and thereby could increase thromboxane, to cause vasoconstriction in the placenta. This study was performed to test the hypothesis that peroxides would produce vasoconstriction in the human placenta by stimulating thromboxane production. Isolated human placental cotyledons were perfused for 20-minute intervals with 100 mumol/L t-butyl hydroperoxide alone, and during and after perfusion with low-dose aspirin (5 x 10(-5) mol/L) (n = 6) or the thromboxane receptor blocker SQ 29,548 (n = 2). Krebs-Ringer-bicarbonate buffer gassed with 95% oxygen and 5% carbon dioxide was used for the perfusion buffer. Perfusion pressure was monitored continuously, and effluent flow rates were measured during each experimental treatment. Maternal and fetal effluent samples were analyzed for thromboxane B2 and 6-keto-prostaglandin F1 alpha. Compared with control Krebs-Ringer-bicarbonate buffer perfusion, peroxide perfusion significantly increased (p < 0.05) vascular resistance (14 +/- 2 vs 25 +/- 3 mm Hg.min/ml, mean +/- SE, respectively), thromboxane B2 secretion (fetal 0.20 +/- 0.04 vs 1.65 +/- 0.26 ng/min, maternal 4.8 +/- 1.5 vs 8.1 +/- 2.1 ng/min) and 6-keto-prostaglandin F1 alpha secretion (fetal 21 +/- 5 vs 60 +/- 1.8 pg/min, maternal nondetectable). Peroxide perfusion increased the thromboxane B2/6-keto-prostaglandin F1 alpha ratio threefold on the fetal side. Subsequent perfusion with aspirin significantly blocked the peroxide-induced vasoconstriction (13 +/- 1 mm Hg.min/ml during aspirin + peroxide) and the peroxide-induced increase in the secretion of thromboxane B2 (fetal 0.52 +/- 0.12 ng/min, maternal 2.0 +/- 0.3 ng/min) and 6-keto-prostaglandin F1 alpha (fetal 30 +/- 8 pg/min). After perfusion with aspirin the thromboxane B2/6-keto-prostaglandin F1 alpha ratio declined. When the thromboxane receptor blocker was used instead of aspirin, maternal and fetal secretion rates of thromboxane were still significantly increased by peroxide perfusion, but there was no change in perfusion pressure or vascular resistance. (1) Peroxide induces placental vasoconstriction coincident with increased secretion of thromboxane; (2) low-dose aspirin blocks both increased thromboxane secretion and vasoconstriction, whereas a thromboxane receptor antagonist allows increased thromboxane secretion but prevents peroxide induced vasoconstriction; (3) therefore, peroxide induces vasoconstriction by stimulating thromboxane synthesis.