Hemodynamic and anti-remodelling effect of the Rho kinase inhibitor Y-27632 in the monocrotaline pulmonary arterial hypertension rat model

Abstract

Introduction: Rho-kinases (ROCK) serve as a point of convergence of various signalling cascades in the pathogenesis of pulmonary arterial hypertension (PAH) and plays a role in vasoconstriction induced by endothelin. We assessed the effect of the ROCK inhibitor Y-27632 in monocrotaline (MCT)-induced PAH in rats, an experimental model utilized to mimic clinical features of PAH. Methods and results: Male Wistar rats were randomized into three groups: sham (CTRL, n=6); MCT (n=15); MCT+ Y-27632 (n=15). Two weeks after a single subcutaneous (s.c.) injection of monocrotaline (MCT, 60 mg/Kg), rats received a once daily treatment with Y-27632 (p.o., 100 mg/Kg). After 28 days from the MCT induction, rats were subjected to haemodynamic measurements. Right ventricle (RV) pressure was increased in MCT rats (61±7 vs 23±1 mm Hg). Y-27632 treatment attenuated this change (MCT+Y-27632: 33±2 mm Hg) without affecting systemic pressure (CTRL: 124±8; MCT 105±6; MCT+ Y-27632: 96±6 mm Hg). MCT-group developed RV hypertrophy which was not significantly counteracted by Y-27632. Morphometric analysis revealed that MCT increased distal pulmonary artery muscularization (alpha-SMA staining) compared to CTRL-group in pulmonary arteries sub-grouped according to diameter. Treatment with Y27632 significantly reduced the medial thickening of the arterioles, regardless the size (61-100 μm diameter: 23% reduction, 101-200 μm diameter: 16% reduction; 201-300 μm diameter: 15% reduction). Conclusions: In the rat MCT model, Y-27632 ameliorates hemodynamic parameters and pulmonary vascular remodelling, thus suggesting a therapeutic potential for pharmacological inhibition of ROCK.