INHIBITORS OF NITRIC-OXIDE SYNTHASE SELECTIVELY REDUCE FLOW IN TUMOR-ASSOCIATED NEOVASCULATURE

1 The effects of L-arginine analogues, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) and methylene blue on blood flow in a murine adenocarcinoma and melanoma have been investigated. 2 Sponge implants in Balb/c and C57/BL mice were used to host proliferating tumour cells while the washout of Xe-133 was employed to assess local blood flow in the implanted sponges. 3 Pharmacological inhibition of nitric oxide (NO) reduced blood flow in both tumours but this effect was reversed by administration Of L-arginine. 4 In marked contrast, the effect of these same NO inhibitors on the blood flow in sponge-induced non-neoplastic granulation tissue was negligible. 5 These results strongly suggest that: (a) flow in tumour vessels is modulated by nitric oxide which maintains a dilator tone in neoplastic tissue; (b) the constrictor activity (as monitored by an increase in t 1/2 of Xe-133) of NO inhibitors may be attributed to the removal of such dilator tone; (c) many of the abnormalities described in tumour vasculature, such as hyporeactivity or unresponsiveness to vasoactive mediators and maximum vasodilatation, may be due to an increase in NO synthesis in cancers.