REGULATION OF INDUCIBLE NO SYNTHASE EXPRESSION BY ENDOTHELIN IN PRIMARY CULTURED GLIAL-CELLS

Nitric oxide (NO), initially identified as an endothelium-derived rela xing factor, is a molecular mediator that has been implicated in many physiological and pathological processes. In primary cultured rat glia l cells, a combination of inflammatory cytokines (tumor necrosis facto r-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta)) and bacterial lipopolysaccharide (LPS) stimulates production of nitrite via expressi on of the inducible form of nitric oxide synthase (iNOS). In these cel ls, simultaneous addition of endothelin (ET) markedly inhibited TNF-al pha/IL-1 beta-induced and LPS-induced nitrite production and iNOS expr ession, although ET by itself had no effect. The inhibitory effect of ETs appears to be mediated by ETB receptors. Forskolin also inhibited the iNOS expression. By contrast, pretreatment with ET for 24 hours en hanced LPS-induced nitrite production and iNOS expression. This stimul atory effect of ETs was suppressed by calphostin C, a protein kinase C inhibitor, and pretreatment with phorbol ester enhanced LPS-induced i NOS expression. Our findings present the possibility that ET has dual effects on iNOS expression in glial cells.