PTHrP has many important roles in lung development and function. In this study, the vasomotor responses of isolated pulmonary arteries and veins of newborn (7-11 day old) and adult (1 year old) sheep to PTHrP were determined. In vessels constricted with endothelin-1, PTHrP (PTHrP 1-34) caused greater relaxation of veins than of arteries. In both vessel types, relaxation to the peptide was less in adult than in newborn vessels. In newborn lambs, PTHrP-induced relaxation was not affected by removal of endothelium, inhibition of nitric oxide synthase or inhibition of adenylyl cyclases by SQ 22536. However, the relaxation was attenuated by 4-aminopyridine, an inhibitor of voltage-dependent potassium channels, in both arteries and veins, and by charybdotoxin, an inhibitor of calcium-activated potassium channels, in veins. When vessels were saturated with 8-Br-cAMP (3x10^-4 M), to eliminate relaxation mediated by endogenous cAMP, PTHrP-induced relaxation was partially attenuated. In vessels treated with 8-Br-cAMP (3x10^-4 M), 4-aminopyridine but not charybdotoxin, inhibited relaxation induced by PTHrP 1-34 in both arteries and veins. Radioimmunoassay showed that, in the presence of a general inhibitor of phosphodiesterases, PTHrP caused a concentration-dependent increase in the intracellular cAMP content in arteries and veins, which was largely abolished by SQ 22536. The results of this study demonstrate that PTHrP is a potent vasodilator of pulmonary vessels, with a greater effect in veins than in arteries. Relaxation induced by the peptide contains a cAMP-dependent and a cAMP-independent component. In both arteries and veins, voltage-dependent potassium channels mediate the response to PTHrP, at least in part, in a cAMP-independent fashion; and in veins, calcium-activated potassium channels may be stimulated by the elevation in cAMP levels.