Indomethacin is a Placental Vasodilator in the Dog

Abstract

A B S T R A C T The effect of 8 mg/kg of indomethacin on uterine blood flow, prostaglandin prodtuction, and intraamniotic fluid pressuire was examined in late pregnant dogs. Uterine blood flow was measured with 15 gm radiolabeled microspheres. Becauise we f0)und that a significant percentage of the microspheres shunted through the placental circulation into the lungs, we calcuilated placental blood flow by adding the shunted microspheres through the placenta to the nonshunited microspheres in the placenta. Total uterine blood flow significantly increased from 271±69 ml/min during control period to 371±72 ml/min (P < 0.01) 30 min af ter indomethacin. This increase was attributable to the change in blood flow to the placental circulation (222 ±58 to 325±63 ml/min; P < 0.01). Associated with these hemodynamic changes we f0und an almost complete suppression of uterine prostaglandin E2 prodtuction (1,654±305 to 51±25 pg/ml; P < 0.01) as meastired by gas chromatography-mass spectrometry. In addition, we found that indomethacin treatment restulted in uterine relaxation as measured by intraamniotic fluiid pressure changes (11.2± 1.3 mm Hg to 8.5 +1.2 mm Hg; P < 0.001).We conclude that indomethacin causes an inerease in placental blood flow without any change in flow to the rest of the uterus, and that this dose of' the drug inhibits greater than 95% of uterine prostaglandin production. In addition, indomethacini is responsible for uterine relaxation. The increase in placental blood flow after indomethacin is probably a result of uterine relaxation, which is secondary to prostaglandin synthesis inhibition.

The Failure of Indomethacin to Alter Acth‐induced Adrenal Hyperaemia or Steroidogenesis in the Anaesthetized Dog

“…However, we think it unlikely that the concentration of indomethacin was insufficient to inhibit prostaglandin cyclo-oxygenase in the adrenal gland. The doses of indomethacin used are adequate to inhibit prostaglandin synthesis in the kidney (Nies, Rawl, Cruze, Oates & Frolich, 1978), pregnant uterus (Gerber, Branch, Hubbard & Nies, 1978), and heart (Hintze & Kaley, 1977) of the dog. Concentrations of indomethacin in excess of that needed in man to inhibit platelet and total body synthesis of prostaglandins (Rane, Oelz, Frolich, Seyberth, Sweetman, Watson, Wilkinson & Oates, 1978) were achieved in our experiments.…”

Prostacyclin produced by the pregnant uterus in the dog may act as a circulating vasodepressor substance.

“…The mediator of the decreased peripheral vascular resistance is not known, but prostaglandins have been implicated to play a role in this effect. We have recently reported that the late pregnant uterus in the dog is capable of synthesizing large amounts ofprostaglandin E2 (PGE2)' which is a potent vasodepressor agent (2). Even though the uterine venous levels of PGE2 were in the nanogram per milliliter range, the arterial PGE2 levels were too low to detect.…”