Activation of G-Protein Coupled Estrogen Receptor Reduces Cardiac and Skeletal Muscle Dysfunction in Female Rats With Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1) and is associated with cardiac and skeletal muscle dysfunction. Hypothesis: Herein, the activation of a new estrogen receptor (GPR30) by the agonist G1 was evaluated in monocrotaline (MCT)-induced PH female rats. Methods: Depletion of estrogen was induced by bilateral oophorectomy (OVX) in female Wistar rats (12 wks old). Experimental groups included the SHAM or OVX that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction followed by administration of vehicle or G1, (400 μg/kg/day s.c.) for 14 days after the onset of disease (n=7 per group). Hemodynamic parameters were determined by transthoracic echocardiography. The effects of G1 in the maintenance of exercise capacity and skeletal muscle function were investigated using a treadmill test to observe the time to exhaustion and evaluating the contractile properties of electrically stimulated soleus (SOL) muscle. Results: MCT injection and estrogen loss led to a significant decrease in pulmonary acceleration time (PAT) and an increase in RV free wall thickness and MCT-related changes were attenuated by treatment with G1 (Table 1). Right ventricular systolic pressure (RVSP) was higher in MCT-injected rats and the magnitude of this increase in OVX group was significantly higher than that in SHAM group and G1 normalized it (Table 1). Combination of estrogen loss and MCT also reduced treadmill time to exhaustion in PH rats ( P P Conclusions: G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in aging females.