title: AA-2414, an antioxidant and thromboxane receptor blocker, completely inhibits peroxide-induced vasoconstriction in the human placenta.
abstract: 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 microM), KRB buffer, and KRB buffer containing Px to which progressively increasing concentrations of AA-2414 were added (1 x 10(-8) to 1 x 10(-4) mol/l). In study 2, placental cotyledons (n = 6) were perfused with control KRB buffer, Px alone, KRB buffer, 1 x 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 F1alpha. 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 x 10(-5) mol/l completely inhibited Px-induced vasoconstriction and increases in lipid peroxide and TXB2 secretion rates, but only partially inhibited the increase in 6-keto prostaglandin F1alpha 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.
authors.affiliation: Departments of Obstetrics and Gynecology, and Physiology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia, USA. swwalsh@hsc.vcu.edu
authors.forename: S W
authors.initials: SW
authors.lastname: Walsh
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Killian
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010545:Peroxides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D011247:Pregnancy; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D013929:Thromboxane B2 / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D006538:Heptanoic Acids; D010545:Peroxides; D017482:Receptors, Thromboxane; C060230:seratrodast; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha