Rho-kinase (ROCK) inhibitors prevent pulmonary hypertension (PHT) in adult rodents, but little is known about their effects on the neonatal lung. Our objective was to examine the effects of ROCK inhibition on chronic hypoxia (CH)-induced PHT and abnormal lung structure in the neonatal rat. Pups were exposed to air or CH from postnatal d 1-14 while receiving Y-27632 (5 or 10 mg ⅐ kg), or saline intraperitoneally. Relative to air, CH-exposed pups had increased pulmonary vascular resistance, right ventricular hypertrophy, arterial medial wall thickening, and abnormal distal airway morphology characterized by septal thinning and decreased secondary septation. Treatment with 10 mg/kg Y-27632 or fasudil attenuated the structural and hemodynamic changes of PHT while having no effect on septal thinning or inhibited secondary septation. In addition, Y-27632 (10 mg/kg) and fasudil augmented CH-induced somatic growth restriction. Pulmonary arteries of CH-exposed pups had increased ROCK activity, up-regulated expression of PDGF-BB and increased smooth muscle DNA synthesis, all of which were attenuated by treatment with 10 mg/kg Y-27632. Systemically administered ROCK inhibitors prevented PHT in the CH-exposed neonatal rat but at the cost of inhibited somatic growth. Limiting effects on vascular remodeling likely resulted, in major part, from attenuated vascular PDGF-BB/-receptor signaling. (Pediatr Res 67: 177-182, 2010) C hronic pulmonary hypertension (PHT) that has its origins during fetal or neonatal life is characterized pathologically in both humans (1) and experimental animals (2) by sustained vasoconstriction and rapid remodeling of pulmonary resistance arteries in which hyperplasia of medial wall smooth muscle is a major feature (3,4). Recent studies have implicated the RhoA/Rho-kinase (ROCK) pathway as central to the initiation and perpetuation of chronic PHT (5), based largely on the effects of two ROCK-specific kinase inhibitors: Y-27632 and fasudil (6). ROCK inhibitors have been reported to inhibit pulmonary artery myogenic responses in hypoxiaexposed adult rats (7) and fetal sheep (8) and to reverse sustained pulmonary vasoconstriction in response to hypoxia (9,10), bleomycin (10), or the infusion of vasoconstrictors, such as endothelin-1 (11). Systemic administration of ROCK inhibitors, commenced at the onset of injury, has been reported to prevent PHT induced either by hypoxia (9) or monocrotaline (12) in adult rodents. Finally, pilot studies in humans have shown that systemically administered fasudil acutely decreases pulmonary arterial pressure in adults with idiopathic PHT (13) and in children with PHT secondary to congenital heart disease (14). Together, these findings indicate that ROCK inhibitors hold great promise as a uniquely effective treatment for chronic PHT, however, little is known about their effects on the neonatal lung and pulmonary vasculature.We have recently reported evidence of RhoA/ROCK pathway activation in the pulmonary arteries of neonatal rats with NO-unresponsive chronic ...