To determine the effect of alveolar hypoxia and consequent increased pulmonary vascular tone on the responsiveness of the neonatal pulmonary circulation, we studied the local pulmonary vascular effects of acetylcholine, bradykinin, and histamine in the normoxic and hypoxic newborn lamb. Right and left pulmonary flows were continuously monitored from chronically implanted electromagnetic flow probes, agents were injected into only one lung, and changes in the proportion of pulmonary blood flow directed to the injected lung (Qinj/QT) provided a measure of active local pulmonary vascular constriction or dilation. At maximally tolerated doses, hypoxia enhanced the dilatory effects of acetylcholine and diminished the constrictor effects of histamine but hypoxia had a minimal effect on the maximal dilatation induced by bradykinin. Hypoxia did appear to lower the threshold dose for bradykinin's effects. These results demonstrate that base-line conditions may qualitatively alter the responsiveness of the neonatal pulmonary circulation to several drugs. In these agents, increased base-line tone generally augmented dilatory effects and diminished constrictor effects. However, the lack of such an effect on the dilator response to a high dose of bradykinin suggests the possibility that hypoxic-induced changes in pulmonary vascular responsiveness may not be entirely passive. Further, these results do not support the hypothesis that hypoxic-induced vasoconstriction is mediated by decreased production of bradykinin.