Mechanisms underlying activation of soluble guanylate cyclase by the nitroxyl donor Angeli's salt.
نویسندگان
چکیده
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) approximately 10 nM, maximum at 1 microM) that was accompanied by the formation of NO. DTT (2 mM) inhibited the effects of <10 microM AS but led to sGC activation and NO release at 0.1 mM AS even without SOD. AS had no effect on ferric sGC, excluding activation of the oxidized enzyme by HNO. The NO scavenger carboxy-PTIO inhibited endothelial cGMP accumulation induced by AS in the presence but not in the absence of SOD (EC(50) approximately 50 nM and approximately 16 microM, respectively). Carboxy-PTIO (0.1 mM) inhibited the effect of <or=10 microM AS in the presence of SOD but caused NO release from 0.1 mM AS in the absence of SOD. These data indicate that AS activates sGC exclusively via NO, formed either via SOD-catalyzed oxidation of HNO or through a minor AS decomposition pathway that is unmasked in the presence of HNO scavenging thiols.
منابع مشابه
Mechanisms underlying activation of soluble guanylate cyclase by the HNO donor Angeli's Salt *
متن کامل
Nitroxyl (HNO) Stimulates Soluble Guanylyl Cyclase to Suppress Cardiomyocyte Hypertrophy and Superoxide Generation
BACKGROUND New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO• attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulat...
متن کاملNO- activates soluble guanylate cyclase and Kv channels to vasodilate resistance arteries.
Nitric oxide (NO) plays an important role in the control of vascular tone. Traditionally, its vasorelaxant activity has been attributed to the free radical form of NO (NO*), yet the reduced form of NO (NO-) is also produced endogenously and is a potent vasodilator of large conduit arteries. The effects of NO- in the resistance vasculature remain unknown. This study examines the activity of NO- ...
متن کاملNitroxyl anion donor, Angeli's salt, does not develop tolerance in rat isolated aortae.
The nitroxyl anion (HNO) is emerging as a novel regulator of cardiovascular function with therapeutic potential in the treatment of diseases such as heart failure. It remains unknown whether tolerance develops to HNO donors, a limitation of currently used nitrovasodilators. The susceptibility of the HNO donor, Angeli's salt (AS), to the development of vascular tolerance was compared with the NO...
متن کاملIntracellular but not extracellular conversion of nitroxyl anion into nitric oxide leads to stimulation of human neutrophil migration.
Considerable controversy exists in the literature with regard to the nature of the agent mediating the biological effects of nitroxyl (NO-) donors. Here it is demonstrated that Angeli's salt (AS), a generator of NO-, enhanced human neutrophil migration. Under aerobic conditions, AS was converted to peroxynitrite to a small extent. However, using methionine, a scavenger of peroxynitrite, it was ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular pharmacology
دوره 76 5 شماره
صفحات -
تاریخ انتشار 2009