Nitric oxide synthase inhibition promotes carcinogen-induced preneoplasticchanges in the colon of rats

L-Arginine is metabolized either to polyamines through arginase and ornithi ne decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, ni trogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels an d ODC activity are high in tumor cells. The aim of this study was to test w hether N-G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, mod ulates colon carcinogenesis. Adult male Wister rats were treated with azoxy methane (AOM, 15 mg/kg ip), a chemical carcinogen, once a week for 2 weeks. One week after the second injection the rats were randomly divided into tw o groups. One group (n = 8) received L-NAME (10 mg/kg body wt/day) in drink ing water. The control group (n = 8) received tap water. After 5 weeks, the rats receiving L-NAME showed enhanced mean basal arterial blood pressure, decreased heart rate, and a significant decrease of the cGMP content in the colonic mucosa, In both groups, AOM induced the formation of colonic aberr ant crypt foci (ACF). In L-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosylme thionine-decarboxylase activity and putrescine concentration were significa ntly increased in the colonic mucosa of L-NAME-treated rats. The data sugge st that L-NAME promotes carcinogen-induced preneoplastic changes in the col on by inhibiting NOS activity and by stimulating polyamine biosynthesis. (C ) 2000 Academic Press.