Investigation of endothelin-1 receptor antagonist bosentan in a rat endometriosis model.

Abstract

The study aimed to investigate the roles of endothelin-1 and endothelin receptors in a rat endometriosis model and to demonstrate how bosentan (BOS), an endothelin receptor blocker, could potentially serve as a novel treatment for endometriosis. Overall, 36 rats were divided into groups as follows: Group 1: Sham, Group 2: endometriosis, Group 3: Sham + BOS100 mg/kg, Group 4: endometriosis + BOS 25 mg/kg, Group 5: endometriosis + BOS 50 mg/kg, and Group 6: endometriosis + BOS 100 mg/kg. In the first laparotomy, an experimental endometriosis model was created by implanting a 0.5 × 0.5 cmpiece of autologous endometrial tissue in Groups 2, 4, 5, and 6. After waiting for 4 weeks, a second laparotomy was performed to measure the endometriotic lesions in Groups 2, 4, 5, and 6. Following the measurements, Groups 4, 5, and 6 received oral administration of BOS at doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg, respectively, for 2 weeks. Three groups received 100 mg/kg of BOS during the same time period. After the drug administration, a third laparotomy was performed, and the endometriotic lesions in Groups 2, 4, 5, and 6 were re-measured. Histopathological, immunohistochemical, biochemical, and molecular analyses of endometriotic lesion samples obtained after the experiment revealed a significant increase in the levels of TNF-α, TGF-β, MMP-9, ET-1, eNOS, VEGF, ETR-A, ETR-B, and MAPkinase in the experimental endometriosis group (Group 2). Conversely, these levels were significantly reduced in the BOS treatment groups (Groups 4, 5, and 6) in a dose-dependent manner compared to Group 2. Similarly, surface area measurements of endometriotic lesions showed a dose-dependent reduction in the BOS-treated groups (Groups 4, 5, and 6). The roles of endothelin-1 and its receptors in the pathophysiology and treatment of the endometriosis model of rats were demonstrated histopathologically, immunohistochemically, biochemically, and molecularly using BOS. This study can shed light on clinical treatment protocols for women with endometriosis.