Effects of Rho-kinase Iinhibition on Established Chronic Hypoxic Pulmonary Hypertension in the Neonatal Rat

Rationale: Vascular remodeling and right-ventricular (RV) dysfunction are features of refractory pulmonary hypertension (PHT) in human neonates. These features are replicated in rats chronically exposed to hypoxia (13% O2), in which increased pulmonary vascular resistance (PVR) was acutely normalized by Y-27632, a Rho-kinase (ROCK) inhibitor, but not by inhaled nitric oxide. Objective: To examine the reversing effects of sustained ROCK inhibition on haemodynamic (RV dysfunction and increased PVR) and structural (RV hypertrophy and arterial wall remodeling) changes of chronic hypoxic PHT. Methods: Rat pups were exposed to air or hypoxia from birth for up to 21 days and received Y-27632 (15 mg/kg/b.i.d.) or vehicle from day 14. Results: Y-27632 normalised RV dysfunction and reversed remodeling secondary to chronic hypoxia. These changes were accompanied by increased apoptosis of smooth muscle and attenuated endothelin-1 expression in pulmonary arteries. Conclusion: ROCK inhibitors hold promise as a rescue therapy for refractory PHT in neonates.MAS