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

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Abstract
A number of structurally distinct superoxide dismutase (SOD) mimetics were examined to determine if they shared the ability of authentic Cu/Zn SOD to produce endothelium‐dependent relaxation of rings of rat aorta by protecting basal nitric oxide from destruction by endogenously produced superoxide anion. MnCl2 (10 nM–100 μM), CuSO4 (100 nM–1 mM) and CuDIPS (Cu [II]‐[diisopropylsalicylate]2; 100 nM–30 μM) each mimicked the ability of Cu/Zn SOD (0.1–300 u ml−1) to produce relaxation of phenylephrine‐precontracted aortic rings in a manner inhibited by endothelial removal or treatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM). In contrast, MnTMPyP (Mn [III] tetrakis [1‐methyl‐4‐pyridyl] porphyrin; 10 nM–30 μM) augmented phenylephrine‐induced contraction and this was blocked by endothelial removal or treatment with L‐NAME (100 μM), consistent with destruction rather than protection of basal nitric oxide activity. Pretreatment with Cu/Zn SOD (250 u ml−1) blocked this augmentation suggesting that it arose paradoxically through destruction of nitric oxide by superoxide anion. The spin trap agents tiron (100 nM–1 mM), tempol (100 nM–1 mM) and PTIYO (4‐phenyl‐2,2,5,5‐tetramethyl imidazolin‐1‐yloxy‐5‐oxide; 100 nM–300 μM) all failed to promote endothelium‐dependent relaxation. In fact, the last two augmented phenylephrine‐induced tone and this was blocked by endothelial removal or treatment with L‐NAME (100 μM), consistent with destruction of basal nitric oxide activity. This destruction was unaffected by pretreatment with Cu/Zn SOD (250 u ml−1) and probably reflected the direct ability of tempol and PTIYO to destroy nitric oxide. Thus, the ideal SOD mimetic for protection of nitric oxide activity in conditions of oxidant stress still awaits development. British Journal of Pharmacology (1999) 127, 1159–1164; doi:10.1038/sj.bjp.0702670

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