Bioactivation of Nitroprusside by Porcine Endothelial Cells

Rochelle, Lori G.; Kruszyna, Harriet; Kruszyna, Robert; Barchowsky, Aaron; Wilcox, Dean E.; Smith, Roger P.

doi:10.1006/taap.1994.1189

Cited by 32 publications

(27 citation statements)

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“…Because in our conditions NO is continuously removed by the stream of helium, the decomposition rate is increased, favoring the escape of NO from the reaction vessel. The remaining 25% of unrecovered NO is very likely to be converted to other metabolic species, such as Fe-NOSR, as demonstrated previously by Rochelle et al (1994) or is conserved as S-nitrosothiols (not determined in this study).…”

Section: Discussionmentioning

confidence: 55%

“…The reductive mechanism in SNP bioactivation has been further confirmed in different cell system models. In particular, Rochelle et al (1994), by incubating SNP with porcine endothelial cells and by using ESR spectroscopy to identify the paramagnetic metabolic species of the drug, demonstrated the formation of the pentacoordinated intermediate and of nitrosylated thiol species (nonheme iron-nitrosyl-sulfur complex, Fe-NOSR), generated by reaction of the tetracoordinated intermediate with membrane thiols. Using a sensitive and specific redox chemiluminescence assay for NO, Kowaluk et al (1992) reported that SNP is readily metabolized to NO in subcellular fractions of bovine coronary arterial smooth muscle and that the dominant site of metabolism is in the membrane fraction.…”

mentioning

confidence: 99%

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Electron Spin Resonance and Chemiluminescence Analyses to Elucidate the Vasodilating Mechanism of Sodium Nitroprusside

Aldini

Pirrone²,

Albertini³

et al. 2006

Molecular Pharmacology

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The aim of this study was to elucidate the vasodilating mechanism of sodium nitroprusside (SNP). To do this, SNP was intravenously infused in pigs (1.67 mol/kg), and the following paramagnetic metabolites were identified by electron spin res , the reduced penta-and tetracoordinated intermediates of SNP, respectively; and 4) methemoglobin (metHb). The results indicate the following: 1) Ϸ17% of the dose is converted to HbFe(II)NO at the end of infusion; 2) NO administered as SNP does not undergo bioinactivation (oxidative metabolism), because no significant increase of met-Hb was observed; 3) the equilibrium involving the paramagnetic species of SNP is shifted toward HbFe(II)NO, because a significant increase of transferrin but no detection of the reduced paramagnetic intermediates of SNP was observed. The results obtained indicate that the hemodynamic effect induced by SNP is not mediated by HbFe(II)NO, at least under physiological conditions; hence, a direct release of NO from SNP in the vascular target should be considered. To demonstrate this mechanism, endothelial cells were incubated with SNP, and the release of NO was determined by a novel chemiluminescence method. The results indicate that the endothelium is able to metabolize SNP, with the formation of stoichiometric amounts of NO. In conclusion, SNP is rapidly metabolized to HbFe(II)NO, but the pharmacological response is mediated by a direct mechanism of NO release of the parent compound at the cellular target.

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Electron Spin Resonance and Chemiluminescence Analyses to Elucidate the Vasodilating Mechanism of Sodium Nitroprusside

Aldini

Pirrone²,

Albertini³

et al. 2006

Molecular Pharmacology

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“…The cell survival without radiosensitizer in normoxia and hypoxia is indicated by arrows transformations through reductases known to activate classical bioreductive cytotoxines (Adams, 1992), because highly polar Snitrosothiols are unlikely to penetrate biological membranes easily (Kowaluk et al, 1990). Instead, activation at the cellular membrane resulting in reductive release of NO or its direct transfer towards thiols and other nucleophilic targets is being considered (Bates et al, 1991;Kowaluk et al, 1992;Rochelle et al, 1994). We found that the generation of NO from SNAP was strongly dependent on cell density, indicating bioreductive catalysis to be a predominant mechanism of NO release.…”

Section: Discussionmentioning

confidence: 62%

“…Some NO donors, such as SNAP and GSNO, have generally been assumed to release NO in a spontaneous manner although the slow decomposition rate of S-nitrosothiols appeared to underestimate their biological effects (Kowaluk and Fung, 1990). In fact, the chemistry of Snitrosothiols containing NO as a nitrosonium cation (Stamler et al, 1992), supports the idea of reductive catalysis of NO release, which may occur on the cellular membrane (Bates et al, 1991;Kowaluk et al, 1990;Rochelle et al, 1994). In the report of Mitchell et al (1996), the possibility of bioreductive generation of NO from SNAP has not been explored, but NO output in a cellfree system was apparently too low to account for radiosensitization.…”

mentioning

confidence: 93%

Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation

Janssens¹,

Verovski²,

Berge³

et al. 1999

Br J Cancer

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Nitric oxide (NO) donors have recently been evaluated as radiosensitizers of hypoxic cells in a model of metabolisminduced hypoxia at high cell densities. Mitchell et al (1993Mitchell et al ( , 1996 demonstrated that 2-(N,N,-diethylamino)-diazenolate-2-oxide-Na + (DEA/NO), SNAP and S-nitroso-L-glutathione (GSNO) at a concentration of 1 mM, radiosensitized Chinese hamster V79 lung fibroblasts to a similar extent as oxygen. Griffin et al (1996) reported comparable activity for DEA/NO and (Z)-1-{N- [3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl-amino}-diazen-1-ium-1,2-diolate (SPER/NO) with enhancement ratios of 2.8Ð3.0 in SCK mammary carcinoma cells exposed to 1Ð2 mM radiosensitizer. Our laboratory investigated the radiosensitizing activity of SNP in a panel of eight human pancreatic tumour cell lines and found an overall enhancement ratio of 1.9 at 0.1 mM (Verovski et al, 1996). At 0.3Ð1 mM, SNP caused almost complete radiosensitization in hypoxic PSN1/ADR cells that was accompanied by restoration of radiation-induced DNA breakage up to the level in aerated cells.These data collectively confirm the high radiosensitizing efficiency of NO donors at 1Ð2 mM and suggest a role of NO in the fixation of DNA damage caused by radiation. Whether DNA is the main target for NO, as was postulated by Howard-Flanders (1957), or whether other mechanisms contribute to the enhanced DNA damage remains unclear. As NO can interact with ironÐsulphur containing enzymes, this may result in the inhibition of cellular respiration and sparing of the natural sensitizer oxygen (Mitchell et al, 1996). This sensitizing effect mediated by residual oxygen can be minimized under hypoxic conditions induced by nitrogen gassing, a general approach to study radiosensitizers. Moreover, the latter model of hypoxia allows the use of a broad range of cell densities, which is a necessary step to establish whether the rate of NO release is enhanced by the presence of cells. The NO donors DEA/NO and SPER/NO are known to liberate NO by a purely spontaneous mechanism (Maragos et al, 1991). Some NO donors, such as SNAP and GSNO, have generally been assumed to release NO in a spontaneous manner although the slow decomposition rate of S-nitrosothiols appeared to underestimate their biological effects (Kowaluk and Fung, 1990). In fact, the chemistry of Snitrosothiols containing NO as a nitrosonium cation (Stamler et al, 1992), supports the idea of reductive catalysis of NO release, which may occur on the cellular membrane (Bates et al, 1991;Kowaluk et al, 1990;Rochelle et al, 1994). In the report of Mitchell et al (1996), the possibility of bioreductive generation of NO from SNAP has not been explored, but NO output in a cellfree system was apparently too low to account for radiosensitization. The same conclusion was drawn for another nitrosonium-like NO donor, SNP, whose bioreductive activation was found to be responsible for radiosensitization (Verovski et al, 1996).The objective of the present study was to examine whether bioreductive release of NO from SNAP...

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“…Upon addition of SNP to tissues, there is formation of nitrosyl-iron complexes with thiols, dinitrosyl-iron complexes, and RSNOs. [80] RSNOs are decomposed by transition metal ions, Cu + and Fe…”

Section: Potential Role Of No Donating Compounds As Tumoricidal Agentsmentioning

confidence: 99%

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

et al. 2015

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N itric oxide (NO) is a free radical with signaling capacity that plays an important role in the cardiovascular, neuronal, and immune systems, among others. NO regulates a number of physiological processes through the activation of two major signaling pathways: The activation of the enzyme guanylyl cyclase to form cGMP and S-nitrosylation, a covalent attachment of an NO moiety to a reactive cysteine residue in peptides and proteins. NO produced by the endothelial isoform of NO synthase (eNOS) regulates blood pressure. NO produced in neurons by the neuronal NOS isoform (nNOS) functions as a neurotransmitter. The constitutively expressed isoforms eNOS and nNOS release low fluxes of NO that are associated with cell protection and proliferation. Inflammatory cytokines and toxins induce the inducible NOS isoform (iNOS) in macrophages. Production of NO under these conditions is much higher compared to its production by constitutive enzymes. [1] Higher NO fluxes such as those produced by iNOS stimulated by inflammatory cytokines in macrophages or generated by millimolar concentrations of NO donors are cytotoxic and promote apoptosis. [2] The constitutive NOS isoforms have been detected in some malignant tumors. Activation of eNOS is involved in the initiation and maintenance of tumor growth in pancreatic cancer cell lines.[3] Tumor progression in prostate cancer is associated with eNOS expression, while malignant melanoma progression is associated with nNOS expression. [4,5] The iNOS isoform is ubiquitously distributed in malignant tumors, but its role in tumor development is highly complex and poorly understood.[6] The expression levels of iNOS and Special EditionCancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes, over-expression and deregulated activation of proto-oncogenes, and inactivation of tumor suppressor genes. These cellular actions occur through stimulation of oncogenic signaling pathways. Nitric oxide (NO) can induce genetic changes in cells and its intracellular generation can lead to tumor formation and progression. It can also promote anti-tumor activities. The pro-and anti-tumor activities of NO are dependent on its intracellular concentration, cell compartmentalization, and cell sensitivity. NO affects a number of oncogenic signaling pathways. This review focuses on two oncogenic signaling pathways: NO-EGFR-Src-FAK and NO-Ras-EGFR-ERK1/2 MAP kinases. In these pathways, low to intermediate concentrations of NO/S-nitrosothiols (RSNOs) stimulate oncogenic signaling, while high concentrations of NO/RSNO stimulate anti-oncogenic signaling. Increasing knowledge on pro-and anti-tumorigenic activities of NO and related reactive species such as RSNOs has fostered the research and synthesis of novel NO-based chemotherapeutic agents. RSNOs, effective as NO donors and trans-nitrosylating agents under appropriate conditions, may operate as potential chemotherapeutic agents. (Biomed J 2015;38:380-388) associat...

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Bioactivation of Nitroprusside by Porcine Endothelial Cells

Cited by 32 publications

References 0 publications

Electron Spin Resonance and Chemiluminescence Analyses to Elucidate the Vasodilating Mechanism of Sodium Nitroprusside

Electron Spin Resonance and Chemiluminescence Analyses to Elucidate the Vasodilating Mechanism of Sodium Nitroprusside

Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

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