Anatomic evidence suggests that leu5-enkephalin (Leu5-enk) may be involved in the physiologic control of pulmonary vascular tone. Information regarding its pulmonary vascular effect is limited; we therefore studied its effect on the immature pulmonary circulation. Normoxic and hypoxic unsedated newborn lambs with chronically implanted flow probes around the right and left pulmonary arteries were used. Leu5-enk was injected into one pulmonary artery only, so that any direct effect of the peptide on the pulmonary vessels could be determined by measuring changes in the ratio of blood flow to the injected versus the non-injected lung. Leu5-enk caused a small but significant increase in pulmonary artery pressure without increasing cardiac output or left atrial pressure (threshold = 1 microgram/kg); it is therefore a pulmonary vasoconstrictor. At a dose of 10 micrograms/kg, Leu5-enk also raised pulmonary artery pressure (20.6 mmHg to 23.9 mmHg; F(8,36) = 15.1 p less than 0.001) and calculated PAR (14.6 to 16.1 units; NS). However, the ratio of blood flow to the two lungs did not change; thus, Leu5-enk does not appear to directly act on pulmonary vessels, but rather through an intermediary to produce pulmonary vasoconstriction. This indirect pulmonary vasoconstriction was blocked by pretreatment with naloxone (3 mg/kg). We conclude that Leu5-enk is a pulmonary vasoconstrictor, albeit a weak one, in the lamb and may therefore play a role in pulmonary vascular homeostasis. This vasoconstriction does not seem to be due to a direct effect on pulmonary vessels by Leu5-enk, but may be effected through a neural or hormonal intermediary.