New Rock Inhibitor Improves Pulmonary Vascular Resistance And Right Ventricle Function In Animal Model Of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterised by increased pulmonary arterial pressure and vascular thickening, which causes RV dysfunction and failure. Current therapies lack efficacy for preventing disease progression and lead to poor survival rate in patients. Rho-activated protein kinases (ROCK) play a key role in smooth muscle contraction and proliferation and cardiomyocyte hypertrophy and survival, which indicate the potential of ROCK inhibitors to treat PAH. This work aims to assess the efficacy of a novel ROCK inhibitor, named LASSBio-2065, on cardiac and vascular function in monocrotaline (MCT)-induced PAH. Intraperitoneal injection of 60 mg/kg MCT induced PAH in Wistar rats, which protocol was approved by the Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. After 2 wks, echocardiography confirmed the PAH and rats were randomly divided in groups and treated with either vehicle or LASSBio-2065 (60 μmol/kg/day, i.p.) for 14 days. At the end of treatment, hemodynamic parameters were evaluated using echocardiography and RV catheterization. Tissues were collected for histologic and morphometric analysis. Data expressed as mean ± SEM was analysed using One-way ANOVA followed by Dunnett post-test. LASSBio-2065 improves pulmonary vascular resistance and RV afterload because the ratio of pulmonary acceleration time-to-total ejection time reduced from 26.7 ± 2.0 to 21.7 ± 1.6 (p< 0.05) and RV output from 64.2 ± 6.1 to 39.1 ± 8.0 (p<0.05). Vascular and cardiac remodelling were prevented by LASSBio-2065, since medial wall thickness of distal pulmonary arterioles reduced and short axis RV-to-LV internal area increased from 85.8 ± 11.4 to 115.2 ± 17.8 (p<0.05). The new ROCK inhibitor also improved the RV diastolic function, restoring both RV end-diastolic pressures increasing from 5.3 ± 0.8 to 11.1 ± 1.9 mmHg (p<0.05) and Tau from 16.9 ± 2.2 to 27.1 ± 2.8 (p<0.05). In conclusion, LASSBio-2065 significantly improved RV function in MCT-induced PAH. In conclusion, the new ROCK inhibitor represents a potential alternative for management of PAH-associated RV dysfunction and remodelling.