Regulation of inducible no synthase expression by endothelin in primary cultured glial cells

Abstract

Nitric oxide (NO), initially identified as an endothelium-derived relaxing factor, is a molecular mediator that has been implicated in many physiological and pathological processes. In primary cultured rat glial cells, a combination of inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)) and bacterial lipopolysaccharide (LPS) stimulates production of nitrite via expression of the inducible form of nitric oxide synthase (iNOS). In these cells, simultaneous addition of endothelin (ET) markedly inhibited TNF-α/IL-1β-induced and LPS-induced nitrite production and iNOS expression, although ET by itself had no effect. The inhibitory effect of ETs appears to be mediated by ET B receptors. Forskolin also inhibited the iNOS expression. By contrast, pretreatment with ET for 24 hours enhanced LPS-induced nitrite production and iNOS expression. This stimulatory effect of ETs was suppressed by calphostin C, a protein kinase C inhibitor, and pretreatrment with phorbol ester enhanced LPS-induced iNOS expression. Our findings present the possibility that ET has dual effects on iNOS expression in glial cells.