The Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats.

Abstract

The Endothelin Receptor Antagonist Macitentan Ameliorates Endothelin-Mediated Vasoconstriction and Promotes Neuroprotection of Retinal Ganglion Cells in Rats. Payton Harris Vignesh Krishnamoorthy Wei Zhang Bindu Kodati Sai Chavala Raghu Krishnamoorthy Dorota L. Stankowska 1. Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth TX 76107 2. Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth TX 76107 Purpose: To determine if dietary administration of the dual ETA/ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 mediated vasoconstriction in Brown Norway rats. Methods: Adult male and female Brown Norway rats 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 mM ET-1 or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out a various time points including 2, 5, 10 and 20 minutes. Following the imaging of the vasculature, treatment of rats was continued for 1 week with either macitentan (5 mg/kg/body weight) in dietary gels or untreated control gels. After euthanizing the rats, retinal flat mounts from the rats were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner. Results: Vasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 45% loss of RGCs which was significantly reduced in macitentan-treated rats and RGC counts were similar to that observed in control retinas. Conclusions: The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction preventing ischemia.