Inhibition of neuronal nitric oxide synthase by 6-nitrocatecholamines, putative reaction products of nitric oxide with catecholamines under oxidative stress conditions.
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 K(i) values of 45 and 52 microM respectively. The nitrocatecholamines inhibited H(2)O(2) production in the absence of L-arginine and tetrahydrobiopterin (BH(4)) (the IC(50) values for 6-nitrodopamine and 6-nitronoradrenaline were 85 and 55 microM respectively) but without affecting cytochrome c reduction. The apparent K(i) values for nitrocatecholamine inhibition of enzyme activation by BH(4) were 18 microM for 6-nitrodopamine and 40 microM for 6-nitronoradrenaline. Both nitrocatecholamines antagonized the dimerization of nNOS induced by BH(4) and by L-arginine, the effect being reversed by BH(4) (more than 10 microM) and L-arginine (e.g. 100 microM). Overall, these results suggest that nitrocatecholamines interfere with nNOS activity by binding to the enzyme in the proximity of the substrate and BH(4)-binding sites near the haem group.
Palumbo
A
A
Zoological Station 'Anton Dohrn', Villa Comunale, I-80121 Naples, Italy.
Astarita
G
G
d'Ischia
M
M
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
C403895:6-nitrodopamine; C100495:6-nitronorepinephrine; D011994:Recombinant Proteins; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C003402:sapropterin; D004298:Dopamine; D009638:Norepinephrine