Header

UZH-Logo

Maintenance Infos

Differential Inhibition of Constitutive and Inducible Nitric Oxide Synthase in Vascular Endothelial Cells by Analogues of Tetrahydrobiopterin


Mueller, Nicolas J; Walter, Roland Β; Linscheid, Philippe; Schaffner, Andreas; Schoedon, Gabriele (2002). Differential Inhibition of Constitutive and Inducible Nitric Oxide Synthase in Vascular Endothelial Cells by Analogues of Tetrahydrobiopterin. Pteridines:n/a.

Abstract

In the vasculature, a physiologic production of nitric oxide (NO) is maintained by endothelial nitric oxide synthase (eNOS). Induction of inducible nitric oxide synthase (ÍNOS) under inflammatory conditions (e.g. septic shock) resulting in high levels of nitric oxide (NO) is believed to be partly responsible for the pathophysiologic changes in the vascular system that occur under inflammatory conditions (e.g. septic shock). Both NOS isoforms are dependent on the obligatory cofactor tetrahydrobiopterin (BH4). We investigated the selectivity and potency of the BH4 analogues 4-amino-BH4 and 5-methyl-BH4 in inhibiting eNOS and iNOS in a murine vascular endothelial cell (MVEC) model expressing either eNOS or iNOS under physiologic and inflammatory conditions, respectively. Exogenous BH4 and its precursor sepiapterin both enhanced physiologic eNOS activity in resting MVEC, while 4-amino-BH4 slightly inhibited eNOS. 5-methyl-BH4 did not have any effect on eNOS. BH4, sepi - apterin, and 5-methyi-BH4 had no effect on iNOS in inflammatory activated MVEC. In contrast, 4-amino-BH4 selectively inhibited iNOS with a potency comparable to the unselective NOS inhibitor Νω-monomethyl-L-argimne (L-NMMA). The present study demonstrates that 4-amino-BH4 selectively and potently inhibits iNOS in vascular endothelial cells, while its effect on eNOS is minimal. The selective inhibition of iNOS is a promising strategy for the treatment of inflammatory conditions with high output of NO. Further in vivo studies are required to determine whether inhibition of NO production by analogues of BH4 offers any advantage compared to inhibition by L-arginine analogues

Abstract

In the vasculature, a physiologic production of nitric oxide (NO) is maintained by endothelial nitric oxide synthase (eNOS). Induction of inducible nitric oxide synthase (ÍNOS) under inflammatory conditions (e.g. septic shock) resulting in high levels of nitric oxide (NO) is believed to be partly responsible for the pathophysiologic changes in the vascular system that occur under inflammatory conditions (e.g. septic shock). Both NOS isoforms are dependent on the obligatory cofactor tetrahydrobiopterin (BH4). We investigated the selectivity and potency of the BH4 analogues 4-amino-BH4 and 5-methyl-BH4 in inhibiting eNOS and iNOS in a murine vascular endothelial cell (MVEC) model expressing either eNOS or iNOS under physiologic and inflammatory conditions, respectively. Exogenous BH4 and its precursor sepiapterin both enhanced physiologic eNOS activity in resting MVEC, while 4-amino-BH4 slightly inhibited eNOS. 5-methyl-BH4 did not have any effect on eNOS. BH4, sepi - apterin, and 5-methyi-BH4 had no effect on iNOS in inflammatory activated MVEC. In contrast, 4-amino-BH4 selectively inhibited iNOS with a potency comparable to the unselective NOS inhibitor Νω-monomethyl-L-argimne (L-NMMA). The present study demonstrates that 4-amino-BH4 selectively and potently inhibits iNOS in vascular endothelial cells, while its effect on eNOS is minimal. The selective inhibition of iNOS is a promising strategy for the treatment of inflammatory conditions with high output of NO. Further in vivo studies are required to determine whether inhibition of NO production by analogues of BH4 offers any advantage compared to inhibition by L-arginine analogues

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

16 downloads since deposited on 04 Oct 2018
9 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:Unspecified
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Life Sciences > Clinical Biochemistry
Language:English
Date:1 January 2002
Deposited On:04 Oct 2018 14:21
Last Modified:13 May 2020 22:25
Publisher:De Gruyter
ISSN:0933-4807
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1515/pteridines.2002.13.4.126
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicencegruyter101515pteridines2002134126 (Library Catalogue)

Download

Green Open Access

Download PDF  'Differential Inhibition of Constitutive and Inducible Nitric Oxide Synthase in Vascular Endothelial Cells by Analogues of Tetrahydrobiopterin'.
Preview
Content: Published Version
Language: English
Filetype: PDF (Nationallizenz 142-005)
Size: 2MB
View at publisher