-Adrenergic agonists are important regulators of perinatal pulmonary circulation. They cause vasodilation primarily via the adenyl cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway. We examined the responses of isolated fourth-generation pulmonary veins of term fetal (145 ± 2 days gestation) and newborn (10 ± 1 days) lambs to isoproterenol, a -adrenergic agonist. In vessels preconstricted with U-46619 (a thromboxane A₂ analog), isoproterenol induced greater relaxation in pulmonary veins of newborn lambs than in those of fetal lambs. The relaxation was eliminated by propranolol, a -adrenergic antagonist. Forskolin, an activator of adenyl cyclase, also caused greater relaxation of veins of newborn than those of fetal lambs. 8-Bromoadenosine 3',5'-cyclic monophosphate, a cell membrane-permeable analog of cAMP, induced a similar relaxation of all vessels. Biochemical studies show that isoproterenol and forskolin induced a greater increase in cAMP content and in adenyl cyclase activity of pulmonary veins in the newborn than in the fetal lamb. These results demonstrate that -adrenergic-agonist-mediated relaxation of pulmonary veins increases with maturation. An increase in the activity of adenyl cyclase may contribute to the change.