Endothelin B (ETB) receptor selective agonist endothelin 3 (ET-3) andmediated RGC death and implication for glaucoma.

Purpose: To determine if dietary administration of the dual ETA/ ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) from cell death following an intravitreal injection of endothelin-1 (ET-1) and endothelin-3 (ET-3) in Brown Norway rats. Methods: Brown Norway rats (n=3 per group) were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days, followed by intravitreal injection of either 4 µl of 500 µM ET-1, ET-3 (2 nmole/eye) or vehicle in one eye. Following the injections, treatments with either macitentan or control gels without macitentan was continued for 7 days. After the treatments, retinal flat mounts were prepared and surviving RGCs were counted in a masked manner. Results: ET-1 produced 46% increase in RGC loss (p< 0.0001), compared to contralateral control eyes in rats 7 days post intravitreal administration. Macitentan treatment modestly protected from RGC loss following intravitreal ET-1 injection (27% RGC loss). ET-3 administration caused a modest increase (23%) in RGC death in this acute model, however, macitentan did not cause any further improvement in RGC survival (25% RGC loss). Conclusion: Both ET-1 and ET-3 mediate RGC loss following intravitreal administration in rats. Endothelin receptor antagonists have the potential to be developed as neuroprotective agents for the treatment of glaucoma.