Cyclosporine enhances alpha1-adrenoceptor-mediated nitric oxide production in C6 glioma cells.
The present study was aimed at elucidating the effect of cyclosporine on phenylephrine-evoked nitric oxide (NO) production in C6 glioma cells using direct electrochemical NO monitoring. Phenylephrine (0.1-10 microM) dose-dependently stimulated NO production (0.8-12.9 microM) and this was blocked by NO synthase inhibitor, prazosin, Ca2+-depletion and Xestospongin C (a blocker of the inositol 1,4,5-trisphosphate (IP3) receptor), suggesting that the alpha1-adrenoceptor signaling pathway mediates NO production in C6 cells. Cyclosporine (approximately 10 microM) failed to evoke NO production but increased phenylephrine-evoked NO production by 20-120% of phenylephrine alone in a dose-dependent manner (1-5 microM). Xestospongin C, at a concentration which showed no effect on phenylephrine-induced NO production, significantly inhibited the cyclosporine-enhanced phenylephrine response. This finding suggests that cyclosporine may increase phenylephrine-induced NO production by accelerating IP3 receptor function in the alpha1-adrenoceptor signaling pathway in C6 cells. This enhanced NO production in glial cells may be operative for the occurrence of cyclosporine neurotoxicity including convulsions and encephalopathy.
Ikesue
H
H
Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Kataoka
Y
Y
Kawachi
R
R
Dohgu
S
S
Shuto
H
H
Oishi
R
R
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016572:Cyclosporine