INCREASE IN EXPERIMENTAL PULMONARY METASTASIS IN MICE BY L-ARGININE UNDER INHIBITION OF NITRIC-OXIDE PRODUCTION BY N-G-NITRO-L-ARGININE METHYL-ESTER

As we have previously reported, intraperitoneal injections of N-G-nitr o-L-arginine methyl ester [L-NAME; a competitive inhibitor of nitric o xide (NO) synthase] before and after the injection of B16 melanoma cel ls through a tail vein increased experimental pulmonary metastasis, wh ile simultaneous injections of L-arginine (a substrate of NO synthase) at a 20-fold higher dose synergistically increased pulmonary metastas is. Our present study was intended to elucidate the mechanisms by whic h L-NAME alone or together with L-arginine increases metastasis. injec tions of L-NAME decreased the serum concentration of nitrite plus nitr ate (metabolites of NO) by about 50%, which was not reversed by simult aneous injections of L-arginine. Injections of L-NAME also decreased t he diameter of arterioles and venules by 20-30%, while simultaneous in jections of L-arginine did not show any significant effect. When colla gen- or ADP-induced platelet aggregation was examined using platelet-r ich plasma, injections of L-NAME showed little effects on platelet agg regation, while simultaneous injections of L-arginine rather suppresse d 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 metasta sis induced by L-NAME can be ascribed partly to the contraction of art erioles 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 productio n through unknown mechanisms. (C) 1998 Wiley-Liss, Inc.