Ni2+, a Double-Acting Inhibitor of Neuronal Nitric Oxide Synthase Interfering with -Arginine Binding and Ca2+/Calmodulin-Dependent Enzyme Activation

2001 ◽  
Vol 285 (1) ◽  
pp. 142-146 ◽  
Author(s):  
Anna Palumbo ◽  
Giuseppe Astarita ◽  
Mauro Picardo ◽  
Marco d'Ischia
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Enzyme Activation ◽  
Oxide Synthase

Inhibition of neuronal nitric oxide synthase by 6-nitrocatecholamines, putative reaction products of nitric oxide with catecholamines under oxidative stress conditions

2001 ◽  
Vol 356 (1) ◽  
pp. 105-110 ◽  
Author(s):  
Anna PALUMBO ◽  
Giuseppe ASTARITA ◽  
Marco d'ISCHIA
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Enzyme Activation ◽  
H2o2 Production ◽  
Reaction Products ◽  
Competitive Inhibitors ◽  
Cytochrome C Reduction ◽  
Ic50 Values ◽  
Oxide Synthase

6-Nitrodopamine and 6-nitronoradrenaline (6-nitronorepinephrine), putative products of the nitric oxide (NO)-dependent nitration of dopamine and noradrenaline, are reported to be reversible, competitive inhibitors of neuronal nitric oxide synthase (nNOS) with Ki values of 45 and 52μM respectively. The nitrocatecholamines inhibited H2O2 production in the absence of l-arginine and tetrahydrobiopterin (BH4) (the IC50 values for 6-nitrodopamine and 6-nitronoradrenaline were 85 and 55μM respectively) but without affecting cytochrome c reduction. The apparent Ki values for nitrocatecholamine inhibition of enzyme activation by BH4 were 18μM for 6-nitrodopamine and 40μM for 6-nitronoradrenaline. Both nitrocatecholamines antagonized the dimerization of nNOS induced by BH4 and by l-arginine, the effect being reversed by BH4 (more than 10μM) and l-arginine (e.g. 100μM). Overall, these results suggest that nitrocatecholamines interfere with nNOS activity by binding to the enzyme in the proximity of the substrate and BH4-binding sites near the haem group.

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