Primary open angle glaucoma (POAG) is a progressive optic neuropathy, characterized, in part by extensive extra cellular matrix remodeling and collapse of the lamina cribrosa (LC). Endothelin-1 (ET-1), a potent vasoactive peptide and its receptors, endothelin receptor A (ET A) and endothelin receptor B (ET B), have been implicated in glaucomatous optic neuropathy. In this study we examined the expression of ET-1 and its receptors in GFAP negative LC cells. RT-PCR analysis revealed that LC cells express both ET A, ET B receptors and prepro- ET-1, the primary gene transcript of ET-1. A dose-dependent increase in intra-cellular calcium concentrations was observed in the presence of 1, 10 and 100 nM ET-1. Increased intracellular calcium concentrations were blocked by the ET A selective antagonist BQ610 but not by the ET B specific antagonist BQ788. Desensitization to ET A-mediated increase in intracellular calcium was observed in LC cells following pre-treatment with ET-1 for 24 h. Western blot analysis of LC cells treated with ET-1 for 24 h revealed a decreased expression of ET A receptor protein at 1, 10 and 100 nM concentrations, while a dose dependent increase in the ET B receptor was observed with a significant increase at 100 nM. Quantitative PCR showed a dose-dependent decrease in ET A receptor mRNA levels and an increase in the mRNA levels of ET B receptors. A Griess colorimetric assay was used to measure the NO released from LC cells and ET-1 induced a dose-dependent increase in NO release which was significant at 100 nM concentration. ET-1 induced NO release was significantly blocked by BQ788, an ET B selective antagonist, and as well as BQ610, an ET A selective antagonist. These results suggested that human lamina cribrosa cells expressed functional ET A and ET B receptors and their expression and function was altered in response to prolong exposure to ET-1. This may have an implication in the normal physiology of LC cells and in POAG subjects where elevated levels of ET-1 could impact LC function.