Endothelins exert pathological effects in the eye and much interest centres on their role in causing retinal neuronal death in ischemic diseases like glaucoma. In the present study the influence of the non-selective endothelin antagonist, sulfisoxazole on raised intraocular pressure-induced ischemia to the rat retina was investigated. Moreover, in vitro studies on primary rat retinal cultures were undertaken to see whether sulfisoxazole is able to blunt the toxic effect of lipopolysaccharide (LPS) to retinal neurones. In order to determine whether sulfisoxazole provides protection to the retina the a- and b-wave amplitudes of the electroretinogram (ERG), the localisation of retinal choline acetyltransferase (ChAT), nitric oxide synthase (nNOS) and Thy-1 and the retinal mRNA levels of Thy-1 and FGF-2 were deduced in retinas subjected to ischemia in the absence or presence of sulfisoxazole. The results showed that the ischemia-induced changes to the a- and b-wave amplitudes of the ERG and changes associated with the localisation of ChAT, nNOS and Thy-1 to be significantly blunted by sulfisoxazole. However, while the ischemia-induced changes to Thy-1 and FGF-2 mRNAs were reduced by sulfisoxazole, the reduction was non-significant. The in vitro studies provided support for the protective effect of sulfisoxazole. Here, it was clearly shown that sulfisoxazole attenuated the elevation of nitric oxide (deduced by measuring nitrite) and the reduction in numbers of GABA-containing neurones caused by LPS. The present study provides evidence for the first time that endothelin antagonist can protect the retina from ischemic-like insults as occurs in glaucoma.