Inhibitors of nitric oxide synthase selectively reduce flow in tumour‐associated neovasculature

Abstract

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 ¹³³Xe 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_½ of ¹³³Xe) 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.