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Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin.
J Biol Chem. 2005 Mar 04; 280(9):7540-9.JB

Abstract

The endogenous methylarginines asymmetric dimethylarginine (ADMA) and N(G)-monomethyl-L-arginine (L-NMMA) regulate nitric oxide (NO) production from neuronal NO synthase (nNOS). Under conditions of L-arginine or tetrahydrobiopterin (BH(4)) depletion, nNOS also generates superoxide, O(2)(.); however, the effects of methylarginines on this O(2)(.) generation are poorly understood. Therefore, we measured the dose-dependent effects of ADMA and L-NMMA on the rate and amount of O(2)(.) production from nNOS under conditions of L-arginine and/or BH(4) depletion, using electron paramagnetic resonance spin trapping. In the absence of L-arginine, ADMA (1 microm) inhibited O(2)(.) generation by approximately 60% from a rate of 56 to 23 nmol/mg/min, whereas L-NMMA (0.1-100 microm) had no effect. L-Arginine markedly decreased the observed O(2)(.) adduct formation; however, O(2)(.) generation from the enzyme still occurs at a low rate (12.1 nmol/mg/min). This O(2)(.) leak is NOS-derived as it is not seen in the absence of calcium and calmodulin and demonstrates that O(2)(.) generation from NOS occurs even when normal substrate/ cofactor levels are present. Under conditions of BH(4) depletion, ADMA had no effect on O(2)(.), whereas L-NMMA increased O(2)(.) production almost 3-fold. This O(2)(.) generation was >90% inhibited by imidazole, indicating that it occurred at the heme center. Thus, methylarginines can profoundly shift the balance of NO and O(2)(.) generation from nNOS. These observations have important implications with regard to the therapeutic use of methylarginine-NOS inhibitors in the treatment of disease.

Authors+Show Affiliations

Cardounel AJ
Davis Heart and Lung Research Institute and the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA. cardounel-1@medctr.osu.edu
Xia Y
No affiliation info available
Zweier JL
No affiliation info available

MeSH

AnimalsArginineBiopterinCalciumCalmodulinCell LineCitrullineDose-Response Relationship, DrugElectron Spin Resonance SpectroscopyHumansMagneticsNitric Oxide SynthaseOxygenRatsSpin TrappingSuperoxidesTime FactorsTransfectionomega-N-Methylarginine

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15574418

Citation

Cardounel, Arturo J., et al. "Endogenous Methylarginines Modulate Superoxide as Well as Nitric Oxide Generation From Neuronal Nitric-oxide Synthase: Differences in the Effects of Monomethyl- and Dimethylarginines in the Presence and Absence of Tetrahydrobiopterin." The Journal of Biological Chemistry, vol. 280, no. 9, 2005, pp. 7540-9.
Cardounel AJ, Xia Y, Zweier JL. Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin. J Biol Chem. 2005;280(9):7540-9.
Cardounel, A. J., Xia, Y., & Zweier, J. L. (2005). Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin. The Journal of Biological Chemistry, 280(9), 7540-9.
Cardounel AJ, Xia Y, Zweier JL. Endogenous Methylarginines Modulate Superoxide as Well as Nitric Oxide Generation From Neuronal Nitric-oxide Synthase: Differences in the Effects of Monomethyl- and Dimethylarginines in the Presence and Absence of Tetrahydrobiopterin. J Biol Chem. 2005 Mar 4;280(9):7540-9. PubMed PMID: 15574418.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin. AU - Cardounel,Arturo J, AU - Xia,Yong, AU - Zweier,Jay L, Y1 - 2004/12/01/ PY - 2004/12/3/pubmed PY - 2005/4/9/medline PY - 2004/12/3/entrez SP - 7540 EP - 9 JF - The Journal of biological chemistry JO - J Biol Chem VL - 280 IS - 9 N2 - The endogenous methylarginines asymmetric dimethylarginine (ADMA) and N(G)-monomethyl-L-arginine (L-NMMA) regulate nitric oxide (NO) production from neuronal NO synthase (nNOS). Under conditions of L-arginine or tetrahydrobiopterin (BH(4)) depletion, nNOS also generates superoxide, O(2)(.); however, the effects of methylarginines on this O(2)(.) generation are poorly understood. Therefore, we measured the dose-dependent effects of ADMA and L-NMMA on the rate and amount of O(2)(.) production from nNOS under conditions of L-arginine and/or BH(4) depletion, using electron paramagnetic resonance spin trapping. In the absence of L-arginine, ADMA (1 microm) inhibited O(2)(.) generation by approximately 60% from a rate of 56 to 23 nmol/mg/min, whereas L-NMMA (0.1-100 microm) had no effect. L-Arginine markedly decreased the observed O(2)(.) adduct formation; however, O(2)(.) generation from the enzyme still occurs at a low rate (12.1 nmol/mg/min). This O(2)(.) leak is NOS-derived as it is not seen in the absence of calcium and calmodulin and demonstrates that O(2)(.) generation from NOS occurs even when normal substrate/ cofactor levels are present. Under conditions of BH(4) depletion, ADMA had no effect on O(2)(.), whereas L-NMMA increased O(2)(.) production almost 3-fold. This O(2)(.) generation was >90% inhibited by imidazole, indicating that it occurred at the heme center. Thus, methylarginines can profoundly shift the balance of NO and O(2)(.) generation from nNOS. These observations have important implications with regard to the therapeutic use of methylarginine-NOS inhibitors in the treatment of disease. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15574418/Endogenous_methylarginines_modulate_superoxide_as_well_as_nitric_oxide_generation_from_neuronal_nitric_oxide_synthase:_differences_in_the_effects_of_monomethyl__and_dimethylarginines_in_the_presence_and_absence_of_tetrahydrobiopterin_ DB - PRIME DP - Unbound Medicine ER -