Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aorta

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Abstract
The potential role of copper (Cu2+) in modulating the activity of nitric oxide synthase (NOS) and guanylyl cyclase (GC) was investigated by use of diethyldithiocarbamic acid (DEDCA), a high affinity Cu2+ chelator. DEDCA 100 μM inhibited sodium nitroprusside (SNP; 0.005–10 μM)‐evoked relaxation of rat isolated aortic rings precontracted with 3 μM phenylephrine (PE). A lower concentration of DEDCA (10 μM) did not significantly attenuate SNP‐evoked responses but did inhibit relaxation to the endothelium‐dependent dilator, A23187 (0.01–10 μM). The presence of 100 μM Cu2+, but not 100 μM Fe2+, alone enhanced A23187‐ and SNP‐evoked relaxation of aortae precontracted with PE. The inhibitory effect of DEDCA on SNP‐ and A23187‐induced relaxation was reversed by equimolar concentrations of Cu2+ but not Fe2+, indicating that DEDCA does not act via removal of haem‐iron from the NOS and GC complexes. Superoxide dismutase (30 μ ml−1) was without effect on the inhibition of DEDCA relaxation induced by either SNP or A23187 in aortae precontracted with PE. When assessed by radioimmunoassay, DEDCA inhibited SNP‐ and A23187‐stimulated cyclic GMP formation with IC50 values of 0.5 μM and 50 μM, respectively. These data demonstrate that Cu2+ plays a role in controlling NOS and GC activity in the rat aorta. British Journal of Pharmacology (1997) 121, 345–350; doi:10.1038/sj.bjp.0701144