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

Abstract

PurposeTo determine if dietary administration of the dual ETA/ ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats. MethodsAdult 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 l of 500 M ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner. ResultsVasoconstrictive 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 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas. ConclusionsET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. 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.