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Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ET A Receptors

2005; Cadmus Press; Volume: 46; Issue: 12 Linguagem: Inglês

10.1167/iovs.05-0785

1552-5783

Takatoshi Kobayashi, Hidehiro Oku, Masayuki Fukuhara, Shota Kojima, Asako Komori, Masaki Ichikawa, Kozo Katsumura, Masato Kobayashi, Tetsuya Sugiyama, Tsunehiko Ikeda,

Glaucoma and retinal disorders

purpose. To determine the modification of the glutamate-induced death of retinal neurons by endothelin (ET)-1. methods. Cultured retinal neurons from fetal rats were exposed to glutamate (1.0 mM) alone or glutamate with ET-1 (10−10–10−7M) for 10 minutes. Neuronal death was assessed by the trypan blue exclusion or TUNEL assays at 2, 6, and 24 hours after the exposure. The effects of adding BQ-123 or BQ-788, ETA, and ETB receptor antagonists, respectively, in combination with ET-1 was also assessed. results. Immunohistochemical analyses showed that the ETs as well as ETA and ETB receptors were expressed on cultured retinal neurons consisting mainly of amacrine cells. A brief exposure of the cultured retinal neurons to glutamate alone significantly increased the number of dead cells, and the addition of ET-1 with glutamate caused a further significant increase in retinal neuronal death compared with the cells exposed to glutamate alone. A significant increase in neuronal death was detected at doses of 10 nM of ET-1 and higher after a 24-hour exposure (P < 0.05, Dunnett), whereas brief exposure of neurons to up to 1 μM ET-1 alone did not cause delayed cell death of neurons. BQ-123 (10 nM) suppressed the enhancement of retinal toxicity caused by ET-1 (10 nM), whereas BQ-788 had no significant effect. conclusions. These results indicate that ET-1 enhances glutamate-induced retinal cell death, possibly through ETA receptors. ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions.