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

Abstract

The effects of l‐arginine analogues, NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐monomethyl‐l‐arginine (l‐NMMA) and methylene blue on blood flow in a murine adenocarcinoma and melanoma have been investigated. 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. Pharmacological inhibition of nitric oxide (NO) reduced blood flow in both tumours but this effect was reversed by administration of l‐arginine. In marked contrast, the effect of these same NO inhibitors on the blood flow in sponge‐induced non‐neoplastic granulation tissue was negligible. 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 t½ 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. 1992 British Pharmacological Society