Nitric oxide enhances MPP(+)-induced hydroxyl radical generation via depolarization activated nitric oxide synthase in rat striatum.
We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.
Obata
T
T
Department of Pharmacology, Oita Medical University, Hasama-machi, 879-5593, Oita, Japan. tobata@oita-med.ac.jp
Yamanaka
Y
Y
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006540:Herbicides / Q000494:pharmacology*; D062385:Hydroxybenzoates / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D017551:Microdialysis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000201:enzymology* / Q000503:physiopathology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D006540:Herbicides; D062385:Hydroxybenzoates; D007502:Iron Chelating Agents; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D000493:Allopurinol; C009135:2,3-dihydroxybenzoic acid; D007501:Iron; D019001:Nitric Oxide Synthase; D015655:1-Methyl-4-phenylpyridinium; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine