In pulmonary hypertension, systemic infusion of adrenomedullin (ADM), a potent vasodilator peptide, leads to pulmonary vasodilatation. However, systemic blood pressure declines alike. The present study investigated the effect of aerosolized ADM on pulmonary arterial pressure in surfactant-depleted newborn piglets with pulmonary hypertension. Animals randomly received aerosolized ADM (ADM, n ϭ 6), aerosolized ADM combined with intravenous application of N G -nitro-L-arginine methylester to inhibit nitric-oxide (NO) synthases (ADM ϩ L-NAME, n ϭ 5), or aerosolized normal saline solution (control, n ϭ 6). Aerosol therapy was performed in 30-min intervals for 5 h. After a total experimental period of 8 h, mRNA expression of endothelial and inducible NO synthase and endothelin-1 (ET-1) in lung tissue was quantified using TaqMan real-time polymerase chain reaction. Aerosolized ADM reduced mean pulmonary artery pressure (MPAP) compared with control (p Ͻ 0.001; at the end of the study, ⌬-MPAP Ϫ13.5 Ϯ 1.4 versus Ϫ6.2 Ϯ 2.4 mm Hg). PaO 2 significantly increased in the ADM (⌬PaO 2 243.3 mm Hg) and the ADM ϩ L-NAME group (⌬PaO 2 217.4 mm Hg) compared with the control group (⌬PaO 2 82.9 mm Hg; p Ͻ 0.001). Aerosolized ADM did not influence mean systemic arterial pressure (baseline 63.2 Ϯ 2.7 versus end of the study 66.3 Ϯ 6.5 mm Hg; not significant). NO synthases gene expressions were 20 to 30% lower with ADM compared with control. ET-1 gene expression was significantly reduced (Ͼ50%) after ADM aerosol therapy (p Ͻ 0.001). Aerosolized adrenomedullin significantly reduced MPAP without lowering the systemic arterial pressure and improved profoundly the arterial oxygen tension. This effect seems to be mediated at least in part by the reduction of ET-1.