A collaborative research project between the University College London, England, and Actelion Pharmaceuticals Ltd. in Switzerland found that the drug macitentan, an endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension in connective tissue diseases, both prevents and treats pulmonary hypertension (PH) in transgenic mice.
The study, “Macitentan Responsiveness Supports the Validity of a Murine Model of Pulmonary Hypertension in Scleroderma Associated with Altered Tgfbeta/BMPR2 Signaling,” was presented at the 2015 ACR/ARHP Annual Meeting.
Pulmonary hypertension is characterized by narrowed and blocked blood vessels in the lung airways, leading to elevated pulmonary arterial pressures. It is induced by uncontrolled growth of endothelial cells that yield thick and dense smooth muscle in lung airways.
Previous studies by the researchers showed that imbalance between the growth factors known as TGFbeta and BMPRII contribute to the development of PH following an injury in the pulmonary interior lining vessels.
Transgenic mice and controls were administrated an experimental drug, semaxanib, to induce an injury to the interior lining of the blood vessels and PH in transgenic mice. To test both prevention and treatment, eight mice in each group were treated daily either with macitentan or vehicle from either two days before or eight days after administration of semaxanib.
In each group, development of PH was studied by examining vessel architecture, in vivo blood flow, and right ventricular mass index measurements after the course of three weeks of therapy.
The results suggest that all the transgenic mice treated with semaxanib developed an inflammation in the interior lining of their blood vessels as well as increased volumes of the smooth muscle tissue. The transgenic mice receiving vehicle had elevated right ventricle mass index when compared to other groups.
On the other hand, administration of macitentan to the transgenic mice treated with semaxanib led to normal RV mass. And the transgenic mice treated with semaxanib that developed elevated right ventricle systolic pressure was corrected by macitentan without noticeable variations in blood pressure.
Other results suggest that when compared to controls, lung fibroblasts of the transgenic mice showed increased cellular signaling and depleted quantities of cellular components following the administration of macitentan, and transgenic mice treated with vehicle showed 21 percent of their vessels with pulmonary arterial occlusion. Finally, gene expression analysis revealed changes in the key genes linked to remodeling and failure of the cardiac muscle.
These findings suggest that macitentan prevented and treated the development of PH in the transgenic mouse model, paving the way for continued research to see if macitentan would have the same effect in humans.