Cyclosporine enhances alpha(1)-adrenoceptor-mediated nitric oxide production in C6 glioma cells

The present study was aimed at elucidating the effect of cyclosporine on ph enylephrine-evoked nitric oxide (NO) production in C6 glioma cells using di rect electrochemical NO monitoring. Phenylephrine (0.1-10 muM) dose-depende ntly stimulated NO production (0.8-12.9 muM) and this was blocked by NO syn thase inhibitor, prazosin, Ca2+-depletion and Xestospongin C (a blocker of the inositol 1,4,5-trisphosphate (IP3) receptor), suggesting that the alpha (1)-adrenoceptor signaling pathway mediates NO production in C6 cells. Cyc losporine (similar to 10 muM) failed to evoke NO production but increased p henylephrine-evoked NO production by 20-120% of phenylephrine alone in a do se-dependent manner (1-5 muM) Xestospongin C, at a concentration which show ed no effect on phenylephrine-induced NO production, significantly inhibite d the cyclosporine-enhanced phenylephrine response. This finding suggests t hat cyclosporine may increase phenylephrine-induced NO production by accele rating IP3 receptor function in the alpha (1)-adrenoceptor signaling pathwa y in C6 cells. This enhanced NO production in glial cells may be operative for the occurrence of cyclosporine neurotoxicity including convulsions and encephalopathy. (C) 2000 Elsevier Science B.V. All rights reserved.