Indomethacin-induced pulmonary vasoconstriction in the conscious newborn lamb

The pulmonary vascular effects of indomethacin were studied in chronically-instrumented conscious newborn lambs, 2-12 wk old. Flows were measured in right and left pulmonary arteries; indomethacin was injected into only one lung; and constriction or dilation was assessed from the proportion of pulmonary flow directed to the injected vs. the noninjected lung. Indomethacin was a pulmonary vasoconstrictor in all animals, its threshold dose being 0.01 mg/kg. The constriction after a dose of 0.1 mg/kg was associated with plasma indomethacin levels sufficient to inhibit prostaglandin (PG) synthesis. However, chronic indomethacin therapy (3 mg/kg per day orally) for 3 days, though resulting in similar plasma indomethacin levels, altered neither base-line pulmonary tone nor the pulmonary vascular responses to hypoxia, acetylcholine, bradykinin, or histamine. Pretreatment with indomethacin did abolish the pulmonary effects of a further intravenous dose of the drug. Our results indicate that production of a pulmonary PG may help to maintain normal vessel relaxation. However, the neonatal lung adapts to chronic inhibition of PG synthesis, maintaining normal vascular tone and homeostasis. Pulmonary PGs may play a role in, but are not essential for, normal neonatal pulmonary vascular control.