Mechanisms Underlying Activation of Soluble Guanylate Cyclase by the Nitroxyl Donor Angeli's Salt

Nitroxyl (HNO) may be formed endogenously by uncoupled nitric-oxide (NO) synthases, enzymatic reduction of NO or as product of vascular nitroglycerin bioactivation. The established HNO donor Angeli's salt (trioxodinitrate, AS) causes cGMP-dependent vasodilation through activation of soluble gua...

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Bibliographic Details
Published in:Molecular pharmacology 2009-11, Vol.76 (5), p.1115-1122
Main Authors: Zeller, Andreas, Wenzl, M Verena, Beretta, Matteo, Stessel, Heike, Russwurm, Michael, Koesling, Doris, Schmidt, Kurt, Mayer, Bernd
Format: Article
Language:English
Subjects:
Animals
Cattle
Cells, Cultured
Enzyme Activation - drug effects
Enzyme Activation - physiology
Guanylate Cyclase - metabolism
Nitric Oxide Donors - pharmacology
Nitrites - pharmacology
Nitrogen Oxides - metabolism
Receptors, Cytoplasmic and Nuclear - metabolism
Soluble Guanylyl Cyclase
Swine
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Summary:Nitroxyl (HNO) may be formed endogenously by uncoupled nitric-oxide (NO) synthases, enzymatic reduction of NO or as product of vascular nitroglycerin bioactivation. The established HNO donor Angeli's salt (trioxodinitrate, AS) causes cGMP-dependent vasodilation through activation of soluble guanylate cyclase (sGC). We investigated the mechanisms underlying this effect using purified sGC and cultured endothelial cells. AS (up to 0.1 mM) had no significant effect on sGC activity in the absence of superoxide dismutase (SOD) or dithiothreitol (DTT). In the presence of SOD, AS caused biphasic sGC activation (apparent EC 50 ∼10 nM, maximum at 1 μM) that was accompanied by the formation of NO. DTT (2 mM) inhibited the effects of
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.109.059915