Abstract

Background:Pulmonary hypertension (PH) is a progressive and potentially fatal condition if left untreated. Currently, only sildenafil and bosentan have been approved by the FDA for the medical treatment of pediatric patients. The availability of bosentan, in a developing country, such as Indonesia, is a challenge.
Aim: to evaluate the effect of sildenafil and metformin on endothelin (ET)-1 levels in the progression of pulmonary hypertension.
Methods: Forthy eight, 12 weeks old, male Wistar rats, weighing 117-193 gram, were injected by monocrotaline (MCT) (60 mg/kg body weight (BW)) subcutaneously. The rats were then randomly assigned to 4 group (control, sildenafil, metformin, sildenafil plus metformin). One day after MCT injection, sildenafil (5mg/kg BW) and metformin (100mg/kg BW) were administered once daily for 21 days. Right heart catheterization was performed on day 22nd after anesthesia with ketamin 50mg/kg BW and xylazin 5mg/kg BW intramuscularly. Blood was taken intracardially for approximately 3.5 mL, and the rats was euthanized. The serum was stored to -20° refrigerator before ELISA analysis. The lung was harvested and paraffin- blocked for latter histology analysis. Blood serum was analyzed for ET-1, and a section of paraffin-blocked lung was stained with hematoxyline-eosin (HE) and α-smooth muscle actin (α-SMA). Intima media thickness (IMT) of 50–200 µm artery and ratio pulmonary artery smooth muscle cells (PASMCs)/fibroblast were analyzed.
Results: The mean pulmonary artery pressure (mPAP) and ET-1 of the treatment group were significantly lower than those of the control group. Intima media thickness was significantly lower in the sildenafil plus metformin group than in the other groups.
Conclusion: sildenafil and metformin alone or in combination improve mPAP and ET-1 levels. Sildenafil plus metformin prevent artery remodeling in PH model.

Key words: sildenafil, metformin, endothelin-1, pulmonary, hypertension