Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension

Rho-kinase-mediated vasoconstriction and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). However, their contribution to the adverse changes in pulmonary blood flow distribution associated with PAH has not been addressed. This study utilizes synchrotron radiation microangiography to assess the specific role, and contribution of, Rho kinase-mediated vasoconstriction and endothelial dysfunction in PAH. Male adult Sprague-Dawley rats were injected with saline (Cont-rats) or monocrotaline (MCT-rats) three weeks before microangiography was performed on the left lung. We assessed dynamic changes in vessel internal diameter (ID) in response to i) the Rho-kinase inhibitor, fasudil (10 mg/kg, i.v.), or ii) acetylcholine (ACh, 3 mug/kg/min), sodium nitroprusside (SNP, 5 mug/kg/min) and N(omega)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, i.v). We observed that MCT-rats had fewer vessels of the microcirculation compared to Cont-rats. The fundamental result of this study is that fasudil improved pulmonary blood flow distribution and reduced pulmonary pressure in PAH rats, not only by dilating already-perfused vessels (ID >100 mum), but also by restoring blood flow to vessels that had previously been constricted closed (ID