Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep

Indomethacin administration has produced decreases in uteroplacental blood flow in several animal studies; therefore, it has been suggested that the maintenance of uterine blood flow is critically dependent on the continued synthesis of vasodilating prostaglandins. However, vasoconstriction following indomethacin administration may be due to mechanisms other than reduced prostaglandin synthesis. We administered indomethacin (2, 5, or 10 mg/kg) intravenously to seven unanesthetized sheep in late pregnancy and determined the time courses of the uteroplacental and systemic hemodynamic responses, comparing these to the concurrent changes in circulating prostaglandins. Indomethacin administration resulted in rapid increases in systemic and uteroplacental vascular resistance (80% to 100%) and mean arterial pressure (∼30%) and in decreases in systemic (∼30%) and uteroplacental (0% to 30%) blood flows within 5 minutes. Vasoconstriction was transient, however, and after 60 minutes there was no evidence of uterine or systemic vasoconstriction, although systemic and uterine plasma prostaglandin levels remained reduced for 180 minutes. Thus substantial inhibition of prostaglandin synthesis existed without evidence of concurrent systemic or uteroplacental vasoconstriction, suggesting that uterine blood flow is not directly dependent on maintained prostaglandin synthesis in unstressed pregnant sheep. Furthermore, the transient indomethacin-induced vasoconstriction may not be due to inhibition of prostaglandin synthesis.