Age-Dependent Effects of Indomethacin on Hypoxic Vasoconstriction in Neonatal Lamb Lungs

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Abstract
Although smooth muscle is abundant in the pulmonary vessels of young animals at birth, it is not clear if these vessels respond more vigorously to hypoxia than the less muscular vessels of older neonates. To determine the effect of age on the pulmonary vascular response to hypoxia during the neonatal period in a single species, we measured the steady-state stimulus-response relationship between inspired oxygen tension (200, 50, 30 and 0 mm Hg) and pulmonary artery pressure-flow curves in isolated blood perfused lungs from 2− to 4− and 12− to 14-day-old lambs. Hypoxic vasoconstriction was attenuated in the younger newborns at an inspired oxygen tension of 50 mm Hg, but not at the other oxygen tensions. To determine if this age-related difference was due to differences in modulation of hypoxic vasoconstriction by cyclooxygenase products, we assayed the metabolite of prostacyclin, 6-keto-prostaglandin F1α in the perfusate and determined the effects of indomethacin (40 μg/ml) on the hypoxic stimulus-response relationship. There was no age-related difference in perfusate concentration of 6-keto-prostaglandin F1α at any oxygen tension. However, indomethacin reversed the age-dependent attenuation of hypoxic vasoconstriction at inspired oxygen tension = 50 mm Hg such that in indomethacin-treated lungs pulmonary vasomotor tone was higher in 2− to 4-day-old lungs than in 12− to 14-day-old lungs. This marked enhancement of hypoxic reactivity by indomethacin in the younger lambs suggests that in isolated neonatal lamb lungs cyclooxygenase products exerted a vasodilatory modulation of hypoxic vasoconstriction that decreased with age.