Neonatal Pulmonary Hypertension Study Reveals Rho-kinase Mediates Right Ventricular Systolic Dysfunction

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Neonatal Pulmonary Hypertension

shutterstock_131404445A new study entitled “Rho-kinase Mediates Right Ventricular Systolic Dysfunction in Rats with Chronic Neonatal Pulmonary Hypertension” published in the October issue of American Journal of Respiratory Cell and Molecular Biology reports that Rho-kinase activity is critical to systolic dysfunction in murine models of neonatal pulmonary hypertension.

Respiratory failure in newborns affects 2% of all live births, and is responsible for more than one-third of all neonatal mortality. Chronic pulmonary hypertension worsens the course of disease, and frequently leads to cardiac right ventricular failure and death.

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Pulmonary hypertension (PH) is characterized by increase blood pressure in lungs vasculature. Thus, so that the blood flow can progress, the heart makes an extra effort to pump the blood to the lungs. As a consequence, the extra workload performed by the heart induces hypertrophy in the hearts’ right ventricle causing right heart failure.

In juvenile rats, systemic treatment with a Rho-kinase inhibitor rescued the systolic dysfunction observed in the right ventricle associated with PH. Rho-kinase has multiple functions including regulation of cellular contraction and motility.

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In this study, the authors aimed to understand how the Rho-kinase inhibitor decreased pulmonary vascular resistance and pressure, right ventricular hypertrophy and systolic dysfunction. In order to accomplish this, they measured right ventricular systolic function in two different experimental setups — in systemically-administered Rho-kinase inhibitors in comparison to inhaled (pulmonary-selective) administration. The authors exposed rat pups to air or hypoxia conditions for 20 days, beginning at day 1 postnatal. At day 21, they received rescued treatments with two forms of the Rho-kinase inhibitor — aerosolized Fasudil hydrochloride or intraperitoneal injection of Y27632. Chronic hypoxia induced increased lRho-kinase activity in the right cardiac ventricle, but no increase was observed for the left ventricle. The inhaled Rho-kinase inhibitor normalized pulmonary vascular resistance and rescued right ventricular hypertrophy and pulmonary arterial wall remodeling. However, an improvement was observed for right ventricular systolic dysfunction. Systemically administered Rho-kinase inhibitor normalized Rho-kinase and phosphodiesterase 5 (PDE5) up-regulation in the right ventricle. Sildenafil treatment (which inhibits PDE5) improved the systolic function in the right ventricle.

The authors concluded that pressure unloading and normalized arterial and cardiac remodeling does not improve systolic function while Rho-kinase activity is still increased. Therefore, their findings suggest that Rho-kinase activity is a key factor of systolic dysfunction in hypoxia conditions.