Abstract: AIM: This study was designed to better understand the effect of chronic treatment with N^ω-nitro-L-arginine methyl ester(L-NAME) with special reference to endothelium-derived nitric oxide (EDNO) synthesis in different arteries. METHODS: The change of the tension of rat artery ring in vitro was determined. The NOS activity was measured by citrulline assay and the histological staining was performed using the methods of hematoxylin-eosin and masson trichrome staining. RESULTS: The blood pressure of rats treated with L-NAME for 3 days and 1 and 8 weeks showed significant increase. Endothelium-dependent relaxation of the aorta induced by acetylcholine (Ach) was reduced after the 3 day treatment, recovered at 1 week and again reduced at 8 weeks. However, the relaxation of small mesenteric arteries was unaltered throughout the experimental period. At 8 weeks, the indomethacin-sensitive endothelium-dependent contraction induced by Ach was noted. Citrulline assay demonstrated that substantial levels of constitutive NO synthase activity remained unchanged in the aorta during the experiments. Chronic treatment with N^ω-nitro-D-arginine methyl ester (D-NAME) also caused perivascular fibrosis as did L-NAME. CONCLUSION: These results suggest that mechanism(s) other than simple inhibition of EDNO synthesis are involved in the chronic cardiovascular effects of L-NAME in the rat mesenteric artery.