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Loss of endothelium‐derived nitric oxide in rabbit aorta by oxidant stress: restoration by superoxide dismutase mimetics
Author(s) -
MacKenzie Andrew,
Martin William
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701899
Subject(s) - chemistry , superoxide dismutase , xanthine oxidase , nitric oxide , tiron , superoxide , dismutase , acetylcholine , oxidative stress , radical , biophysics , biochemistry , pharmacology , enzyme , medicine , organic chemistry , biology
Structurally distinct superoxide dismutase (SOD) mimetics were examined for their ability to protect nitric oxide (NO) from destruction by oxidant stress in rabbit aorta. These were the spin traps, PTIYO (4‐phenyl‐2,2,5,5‐tetramethyl imidazolin‐1‐yloxy‐5‐oxide), tempol (4‐hydroxy 2,2,6,6,‐tetramethylpiperidine‐1‐oxyl) and tiron (4,5‐dihydroxy‐1,3‐benzene‐disulphonic acid), the metal salts, CuSO 4 and MnCl 2 , and the metal‐based agents CuDIPS (Cu (II)‐[diisopropylsalicylate] 2 ) and MnTMPyP (Mn (III) tetrakis [1‐methyl‐4‐pyridyl]porphyrin). Oxidant stress was generated in isolated aortic rings by inactivating endogenous Cu/Zn SOD with diethyldithiocarbamate (DETCA; 60 min) either alone at 3 m M or at 0.3 m M in combination with superoxide generation using xanthine oxidase (XO; 4.8 mu ml −1 ) and hypoxanthine (HX; 0.1 m M ). Acetylcholine (ACh)‐induced relaxation was inhibited by DETCA (3 m M , 60 min) and was not restored by exogenous SOD (250 u ml −1 ), suggesting the oxidant stress was intracellular. MnTMPyP (600 μ M and 1 m M ) and MnCl 2 (100 μ M ) were the only agents to reverse the blockade of ACh‐induced relaxation. Addition of XO/HX to DETCA (0.3 m M )‐treated tissues powerfully impaired ACh‐induced relaxation and exogneous SOD (250 u ml −1 ) fully reversed the blockade, suggesting the oxidant stress was extracellular. CuDIPS (0.1–3 μ M ), CuSO 4 (0.3–3 μ M ), MnCl 2 (1–100 μ M ) and MnTMPyP (100–600 μ M ) also reversed blockade powerfully, tempol (30 μ M –1 m M ) and tiron (0.3–10 m M ) reversed blockade weakly and PTIYO (10–300 μ M ) enhanced the blockade. Thus, MnTMPyP was the only SOD mimetic to restore NO‐dependent relaxation in conditions of both extracellular and intracellular oxidant stress. This agent may, therefore, provide a lead in the development of SOD mimetics for the treatment of pathologies associated with oxidant stress.