AA-2414, an Antioxidant and Thromboxane Receptor Blocker, Completely Inhibits Peroxide-Induced Vasoconstriction in the Human Placenta

We hypothesized that AA-2414, a novel thromboxane receptor blocker with antioxidant properties, would inhibit peroxide-induced vasoconstriction in the isolated perfused human placental cotyledon. In study 1, placental cotyledons ( n = 5) were perfused serially for 20- min intervals with control KrebsRinger-bicarbonate (KRB) buffer, t -butyl hydroperoxide (Px; 100 μM), KRB buffer, and KRB buffer containing Px to which progressively increasing concentrations of AA-2414 were added (1 × 10−8 to 1 × 10−4 mol/l). In study 2, placental cotyledons ( n = 6) were perfused with control KRB buffer, Px alone, KRB buffer, 1 × 10−5 mol/l AA-2414 alone, Px plus AA-2414, and Px alone. Compared with control, perfusion with Px significantly increased perfusion pressure, vascular resistance, and the maternal and fetal secretion rates of lipid peroxides, thromboxane B2 (TXB2) and 6-keto prostaglandin F1α. In study 1, AA-2414 + Px produced a dose-response inhibition of Px-induced increases in perfusion pressure, vascular resistance, and maternal secretion of lipid peroxides and TXB2. In study 2, perfusing AA-2414 at a dose of 1 × 10−5 mol/l completely inhibited Px-induced vasoconstriction and increases in lipid peroxide and TXB2secretion rates, but only partially inhibited the increase in 6-keto prostaglandin F1α secretion. We conclude that AA-2414 inhibited peroxide-induced vasoconstriction in the human placenta, as well as peroxide- induced increases in the placental secretion rates of lipid peroxides and thromboxane, but only partially inhibited peroxide-induced increases in the placental secretion rate of prostacyclin.