The effects of chronic nitric oxide synthase suppression on glioma pathophysiology

Nitric oxide synthase (NOS) is strongly expressed in glioma and has an impo rtant role in tumour blood flow (TBF) regulation. Whether manipulation of N OS function within a tumour can have any therapeutic effect is unknown. Thi s study therefore evaluated the pathophysiological effects of chronic syste mic NOS inhibition on experimental rodent glioma blood flow, growth and nec rosis. To determine the duration and pathophysiological effects of systemic NOS inhibition, N-g-nitro-L-arginine methyl ester (L-NAME) was given to ra ts bearing C6 glioma acutely (single dose i. v., 30 mg kg) or for either 4 or 7 days (i. p. 75 mg kg day) prior to study. TBF and local cerebral blood flow (LCBF) were measured using C-14-iodoantipyrine quantitative autoradio graphy. Tumour volume, tumoural necrosis and tumoural NOS were measured usi ng conventional neuropathology and immunocytochemistry. Acute and 4-day L-N AME administration produced significant TBF reductions (-48 and -39%, respe ctively) with less marked changes in LCBF (-35 and -15%, respectively). Sev en-day L-NAME administration reduced tumour volume (p=0.12), increased tumo ural necrosis (p<0.05), but immunohistochemistry showed no difference in tu moural NOS expression. These results confirm that NOS has a significant rol e in the pathophysiology of experimental glioma, and that in this glioma mo del the effects of chronic systemic NOS inhibition are, for the period unde r study, predominately anti-tumoural. Whether chronic NOS inhibition is use ful as an adjunct in glioma therapy or provides the opportunity for novel t herapeutic approaches requires further study.