NITRIC-OXIDE SYNTHASE IS EXPRESSED IN EXPERIMENTAL MALIGNANT GLIOMA AND INFLUENCES TUMOR BLOOD-FLOW

The distribution and function of nitric oxide synthase (NOS) was studi ed in the rodent C6 implantation glioma model. Using a histochemical s tain for NADPH diaphorase, which colocalises with NOS, morphological s tudies revealed non homogenous staining of the constituent tumour cell s and the neoplastic endothelium. Immunocytochemical staining for macr ophages (ED1, ED2) showed dense positivity at the tumour brain interfa ce with more patchy postivity within the tumour mass. This finding sug gests that both macrophages, which are known to produce large amounts of NO, and the C6 cells contribute to the NADPH diaphorase positivity. Administration of the NOS inhibitor N-g-nitro-L-argine methyl ester ( L-NAME) significantly reduced both tumour (40%) and contralateral loca l cerebral blood flow (20%) compared to control animals. These finding s demonstrate that (i) NOS is present in experimental malignant glioma ; (ii) NO mediated mechanisms contribute to tumour blood vessel dilata tion and blood flow regulation; and (iii) using this model there is a significant differential sensitivity of the tumour and brain parenchym al vascular beds to a NOS inhibitor. Further investigations are requir ed to determine the potential therapeutic and biological relevance of these findings and the relative contributions of tumour cells, neoplas tic endothelium and reactive macrophages to NO mechanisms in gliomas.