The effects of chronic nitric oxide synthase suppression on glioma pathophysiology.
Nitric oxide synthase (NOS) is strongly expressed in glioma and has an important role in tumour blood flow (TBF) regulation. Whether manipulation of NOS function within a tumour can have any therapeutic effect is unknown. This study therefore evaluated the pathophysiological effects of chronic systemic NOS inhibition on experimental rodent glioma blood flow, growth and necrosis. To determine the duration and pathophysiological effects of systemic NOS inhibition, Ng-nitro-L-arginine methyl ester (L-NAME) was given to rats 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 C14-iodoantipyrine quantitative autoradiography. Tumour volume, tumoural necrosis and tumoural NOS were measured using conventional neuropathology and immunocytochemistry. Acute and 4-day L-NAME administration produced significant TBF reductions (-48 and -39%, respectively) with less marked changes in LCBF (-35 and -15%, respectively). Seven-day L-NAME administration reduced tumour volume (p = 0.12), increased tumoural necrosis (p < 0.05), but immunohistochemistry showed no difference in tumoural NOS expression. These results confirm that NOS has a significant role in the pathophysiology of experimental glioma, and that in this glioma model the effects of chronic systemic NOS inhibition are, for the period under study, predominately anti-tumoural. Whether chronic NOS inhibition is useful as an adjunct in glioma therapy or provides the opportunity for novel therapeutic approaches requires further study.
Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
G R
GR
Swaroop
P A
PA
Kelly
H S
HS
Bell
J
J
Shinoda
S
S
Yamaguchi
I R
IR
Whittle
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis; D009368:Neoplasm Transplantation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester