DL0108 suppresses the development of pulmonary arterial hypertension in rats through its protective effect on pulmonary arteries

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a severe disease but in short of an effective drug. DL0108 is a flavonoid discovered by our lab, and is recently found useful in the treatment of PAH. The present study aims to evaluate the potency of DL0108 in PAH rats induced by monocrotaline (MCT).MethodThe PAH rat model was established by subcutaneous injection of 50 mg/kg MCT on day 0. From the second day, 3, 10, or 30 mg/kg DL0108 was respectively administrated (i.p.) daily for 4 weeks in three tested groups, while the model and control group were treated with normal saline. During the experiment, the survival rate and body weight were recorded. At the end of the study, the right ventricular systolic pressure (RVSP) was measured through right cardiac catheterization. The heart ventricle was isolated to calculate the Fulton index (RV/LV+S). The contraction and relaxation of pulmonary artery rings were tested in a classical isolated vessel experiment.ResultOn day 28, the survival rate of the model group was 66.7%. Treatment with 3, 10, or 30 mg/kg DL0108 increased the survival rate to 73.3%, 86.7% and 86.7%, respectively. However, the decrease of body weight induced by PAH was not improved by DL0108. The RVSP of PAH rats in the model group increased from 21.73 to 49.61 mmHg, while the treatment with DL0108 reduced the RVSP to 30.56, 27.42 or 24.9 mmHg, respectively. Meanwhile, DL0108 significantly reduced the right ventricular hypertrophy in a dose‐dependent manner. In the isolated vessel experiment, it was found that 3 and 10 mg/kg DL0108 improved the contraction response of pulmonary artery rings to 10−6 M phenylephrine and the relaxant effect induced by the accumulation of acetylcholine (10−8–10−4 M Ach).ConclusionEarly intervention of PAH rats with DL0108 can delay the progression of the disease and increase the survival rate. The preliminary study indicates that DL0108 protects the function of pulmonary arteries, relieves the remodeling of vessels to control the pressure, and in turn attenuates the injury of heart ventricle. This study contributes to the further development of DL0108 for the treatment of PAH.Support or Funding InformationThis project was supported by grants from the Nation Natural Science Foundation of China (No. 81603101, 81773935, 81573645), Natural Science Foundation of Beijing (No. 7174322) and CAMS Innovation Fund for Medical Sciences (2016‐I2M‐1‐010, 2017‐I2M‐1‐010). The survival rates of PAH rats treated by DL0108.imageThe survival rates of PAH rats treated by DL0108.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.