Effect of benidipine alone and in combination with bosentan and sildenafil in amelioration of pulmonary arterial hypertension in experimental model in rats

Abstract

Pulmonary arterial hypertension (PAH) is a persistent condition affecting the pulmonary arteries' endothelium. Benidipine, a calcium channel blocker, possesses vasodilatory, anti-inflammatory activity, reduces oxidative stress, and inhibits the activity of TGF-β receptor 1 and α-SMA. The present study was designed to investigate the effect of benidipine alone and in combination with bosentan and sildenafil on monocrotaline (MCT)-induced pulmonary hypertension (PH) in a rat model. PAH was induced by single-dose administration of MCT in rats. Animals were randomized into different groups and treated with benidipine alone and in combination with bosentan or sildenafil. Various parameters such as hemodynamic parameters, Fulton's index, oxidative stress parameters, and inflammatory markers were performed. Additionally, histopathology of lung and right ventricular tissue, immunohistochemistry, expression of α-SMA, eNOS, TGF- β, and RT-PCR, and an in-vitro (using HUVECs) study were also carried out. Treatment of benidipine and its combination exhibited better prevention in the elevated right ventricular systolic pressure, right ventricular hypertrophy, rise in oxidative stress and increase in expression of α-SMA and TGF-β receptor 1 compared to MCT control group rats. In HUVEC’s cells, the expression of α-SMA was increased, whereas eNOS decreased after TGF-β exposure and was substantially reversed after pre-treatment with benidipine. We concluded that benidipine and its combination with bosentan and sildenafil exhibit beneficial effects in MCT-induced PAH through the α-SMA/TGF-β/eNOS signaling pathway.