Background—Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia.Methods and Results—Mice homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A−/−) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate inNPR-A+/+mice but notNPR-A−/−animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than didNPR-A+/+mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg · kg−1· d−1). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O2for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration inNPR-A+/+mice, but only RVSP showed evidence of a response to the drug inNPR-A−/−mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted inNPR-A−/−mice.Conclusions—The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.