Effects of superoxide dismutase mimetics on the activity of nitric oxide in rat aorta

1 A number of structurally distinct superoxide dismutase (SOD) mimetics wer e examined to determine if they shared the ability of authentic Cu/Zn SOD t o produce endothelium-dependent relaxation of rings of rat aorta by protect ing basal nitric oxide from destruction by endogenously produced superoxide anion. 2 MnCl2 (10 nM - 100 mu M), CuSO4 (100 nM - 1 mM) and CuDIPS (Cu [II]-[diis opropylsalicylate](2); 100 nM - 30 mu M) each mimicked the ability of Cu/Zn SOD (0.1 - 300 u ml(-1)) to produce relaxation of phenylephrine-precontrac ted aortic rings in a manner inhibited by endothelial removal or treatment with N-G-nitro-L-arginine methyl ester (L-NAME, 100 mu M). 3 In contrast, MnTMPyP (Mn [III] tetrakis [1-methyl-4-pyridyl] porphyrin; 1 0 nM - 30 mu M) augmented phenylephrine-induced contraction and this was bl ocked by endothelial removal or treatment with L-NAME (100 mu M), consisten t with destruction rather than protection of basal nitric oxide activity. P retreatment with Cu/Zn SOD (250 u ml(-1)) blocked this augmentation suggest ing that it arose paradoxically through destruction of nitric oxide by supe roxide anion. 4 The spin trap agents tiron (100 nM(-1) mM), tempol (100 nM - 1 mM) and PT IYO (4-phenyl-2,2,5,5-tetramethyl imidazolin-1-yloxy-5-oxide; 100 nM - 300 mu M) all failed to promote endothelium-dependent relaxation. In fact, the last two augmented phenylephrine-induced tone and this was blocked by endot helial removal or treatment with L-NAME (100 mu M), consistent with destruc tion of basal nitric oxide activity. This destruction was unaffected by pre treatment with Cu/Zn SOD (250 u ml(-1)) and probably reflected the direct a bility of tempol and PTIYO to destroy nitric oxide. 5 Thus, the ideal SOD mimetic for protection of nitric oxide activity in co nditions of oxidant stress still awaits development.