We tested the effects of nebulized nitroprusside (Neb-NP) on pulmonary and systemic hemodynamics during pulmonary hypertension induced by hypoxia or group B streptococci infusion in piglets. Twenty-three anesthetized and mechanically ventilated piglets received Neb-NP under four experimental conditions: 1) normoxia; 2) 15 and 60 min of pulmonary hypertension induced by hypoxia; 3) after pretreatment with dipyridamole; 4) pulmonary hypertension induced by infusion of group B streptococci. In addition, Neb-NP was contrasted to nebulization of tolazoline. During hypoxia-induced pulmonary hypertension, Neb-NP significantly reduced pulmonary artery pressure [PAP; -8.4+/-0.9 (SEM) mm Hg] and pulmonary vascular resistance (-25+/-2.1%) (both p < 0.001), whereas neither systemic arterial pressure nor cardiac output changed significantly. Selective pulmonary vasodilation began within 2 min of the onset of Neb-NP, and did not wane over 1 h. In contrast, within 5 min after Neb-NP was discontinued while hypoxia persisted, PAP rose significantly. Pretreatment with dipyridamole did not enhance the pulmonary vasodilation induced by Neb-NP, but did reduce systemic arterial pressure. Nebulized tolazoline did not reduce PAP significantly, but did lower systemic arterial pressure. Selective pulmonary vasodilation induced by Neb-NP was significantly smaller during group B streptococci-induced versus hypoxia-induced pulmonary hypertension. In sum, Neb-NP produced prompt, significant, selective reduction of PAP in piglets with pulmonary hypertension. Cautious extrapolation of these findings to selected clinical conditions in human infants may be warranted.