Copper induces type II nitric oxide synthase in vivo. Free Radic Biol Med

Intravenous administration of copper (up to a final concentration of ca. 35 _mol/l in the plasma) led to a progressive, dramatic fall of mean arterial pressure in rats. Copper-induced pressure changes were comparable to those elicited by 2 mg/kg LPS, and were greatly prevented by previous infusion of the inducible NOS (NOS-II) inhibitors aminoguanidine or l-N(6)-(L-imino-ethyl)lysine. RT-PCR analysis showed a significant transcriptional induction of NOS-II in a number of tissues, including aorta, liver, and lungs. Immunohistochemistry revealed that NOS-II was massively synthesized in these tissues upon copper or LPS treatment. The protein was active, as revealed by enzymatic assays on lung homogenates and by the large increase of nitrite/nitrate levels in the plasma. Copper-challenged rats displayed elevated plasma levels of TNF_. Extensive formation of nitrotyrosines, indicative of peroxynitrite production, was accompanied by marked morphological changes in examined tissues. Our results clearly show that copper can act as a proinflammatory agent through activation of the nitric oxide pathway, leading to the same pathological frame induced by bacterial lipopolysaccharide.