Copper induces type II nitric oxide synthase in vivo.
Intravenous administration of copper (up to a final concentration of ca. 35 micromol/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 TNFalpha. 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.
Clinical-Experimental Department of Medicine and Pharmacology, University of Messina, Messina, Italy. musci@unime.it
Salvatore
S
Cuzzocrea
Tiziana
T
Persichini
Laura
L
Dugo
Marco
M
Colasanti
Giovanni
G
Musci
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006146:Guanidines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003300:Copper; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine