Increase in experimental pulmonary metastasis in mice by L-arginine under inhibition of nitric oxide production by NG-nitro-L-arginine methyl ester.

As we have previously reported, intraperitoneal injections of NG-nitro-L-arginine methyl ester [L-NAME; a competitive inhibitor of nitric oxide (NO) synthase] before and after the injection of B16 melanoma cells through a tail vein increased experimental pulmonary metastasis, while simultaneous injections of L-arginine (a substrate of NO synthase) at a 20-fold higher dose synergistically increased pulmonary metastasis. Our present study was intended to elucidate the mechanisms by which L-NAME alone or together with L-arginine increases metastasis. Injections of L-NAME decreased the serum concentration of nitrite plus nitrate (metabolites of NO) by about 50%, which was not reversed by simultaneous injections of L-arginine. Injections of L-NAME also decreased the diameter of arterioles and venules by 20-30%, while simultaneous injections of L-arginine did not show any significant effect. When collagen- or ADP-induced platelet aggregation was examined using platelet-rich plasma, injections of L-NAME showed little effects on platelet aggregation, while simultaneous injections of L-arginine rather suppressed platelet aggregation. B16 melanoma cells produced NO in culture, and L-NAME (0.2 mM) decreased NO production without effects on viability. Our results suggest that the increased experimental pulmonary metastasis induced by L-NAME can be ascribed partly to the contraction of arterioles and venules, which is induced by the inhibition of endogenous NO production by L-NAME, and that the synergistic effect of L-arginine on metastasis is related to the inhibition of endogenous NO production through unknown mechanisms.