Metformin Prevents the Development of Monocrotaline-induced Pulmonary Hypertension by Decreasing Serum Levels of Big Endothelin-1

Pulmonary hypertension (PH) is a disease with poor prognosis, and it is characterized by the progressive elevation of pulmonary vascular resistance and pressure. Various factors are associated with the pathology of PH, including AMP-activated protein kinase (AMPK) deficiency. The present study aimed to evaluate the therapeutic effect of metformin, an AMPK activator, in a monocrotaline (MCT)-induced PH rat model. Rats were randomly divided into the following three groups: i) Saline-injected group (sham group); ii) monocrotaline (MCT)-injected group (PH group); iii) MCT-injected and metformin-treated group (MT group). Four weeks following MCT injection, cardiac ultrasonography, invasive hemodynamic measurements, measurement of serum levels of big endothelin-1 (big ET-1) and histological analysis were performed to evaluate the effect of metformin treatment in PH. Pulmonary arterial pressure and serum big ET-1 concentrations were reduced in the MT group compared with the PH group. Medial wall thickness and wall area of the pulmonary arterioles in the MT group were decreased compared with the PH group. Comparing the right heart functional parameters among groups revealed that the acceleration time/ejection time ratio improved in the MT group compared with the PH group. Thus, the present study demonstrated the efficacy of metformin in an MCT-induced PH rat model and suggested that metformin may be a valuable, potential novel therapeutic for the treatment of PH.