ChemInform Abstract: AN UNUSUALLY STABLE THIONITRITE FROM N‐ACETYL‐D,L‐PENICILLAMINE, X‐RAY CRYSTAL AND MOLECULAR STRUCTURE OF 2‐(ACETYLAMINO)‐2‐CARBOXY‐1,1‐DIMETHYLETHYL THIONITRITE

Field, Lora M.; Dilts, Robert V.; Ravichandran, R; Lenhert, P. G.; Carnahan, Gary E.

doi:10.1002/chin.197829195

Cited by 23 publications

(28 citation statements)

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“…2A). With increasing time (8,12, and 24 hours) of cytokine stimulation, iNOS was observed less within the peroxisomes but more in cytoplasmic aggregates, diffusely throughout the cytoplasm and associated with the plasma membrane.…”

Section: Pattern Of Inos Expression Varies With Timementioning

confidence: 94%

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Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

et al. 2002

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Shock states induce the expression of inducible nitric oxide synthase (iNOS) in both Kupffer cells and hepatocytes in the liver, but little is known about its subcellular localization in these cells. Studies were undertaken to characterize the subcellular location of iNOS in hepatocytes in response to sepsis. By immunofluorescence analysis, intraperitoneal challenge with bacterial lipopolysaccharide induced cytosolic iNOS in Kupffer cells but punctate labeling in hepatocytes. Cultured rat hepatocytes exposed to interferon gamma, interleukin 1, and tumor necrosis factor ␣ showed iNOS protein expression within peroxisomes as early as 4 hours after stimulation, as determined by colabeling for catalase or PMP70. To a lesser extent, iNOS was also observed associated with the plasma membrane and in undefined intracellular aggregates. S tudies in the past decade have shown that all nitric oxide synthases (NOS), whether constitutive or inducible, are regulated at transcriptional, posttranscriptional, translational, and posttranslational levels. 1 One important aspect of NOS regulation is its subcellular localization. For example, endothelial NOS is localized to the caveolae of endothelial cells, where direct association with caveolin I regulates enzyme activity. 2 Such localization may enhance NO function by concentrating NO release close to the cell surface. The inducible NOS (iNOS; NOS2) isoform, which contributes to inflammatory processes through high NO output, is regulated positively and negatively by cytokines but can also be controlled posttranslationally by NO and/or its reaction products. 1,3,4 Furthermore, this enzyme is found in both particulate and cytosolic cellular pools. 5 Our interest has focused on the regulation and function of iNOS in the liver. This enzyme is readily upregulated in hepatocytes, 6 and human iNOS expression was first detected in hepatocytes. 7 In vivo studies have shown that the consequences of iNOS up-regulation in liver are dependent on the physiologic or pathologic circumstances. Following conditions associated with severe redox stress, iNOS contributes to hepatocellular damage during hemorrhagic shock or hepatic ischemia/reperfusion. 8,9 In contrast, iNOS-generated NO suppresses hepatocyte apoptosis in endotoxemia 10 and following cytokine exposure. 11 To better understand how iNOS functions within hepatocytes as well as factors that might determine the fate of NO in the liver, we undertook a study to characterize its subcellular localization. We show that iNOS localizes to the peroxisome, plasma membrane, and cytoplasm. Interestingly, increased expression of iNOS is associated with decreased catalase expression.

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Section: Pattern Of Inos Expression Varies With Timementioning

confidence: 94%

“…S-nitroso-N-acetylpenicillamine was synthesized and activity monitored as described. 12 Ethanol stock solutions were prepared at 100 mmol/L, and dilutions were made in culture medium. N-iminoethyl-Lornithine (L-NIO) was from Alexis Co. (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

et al. 2002

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“…Methylene blue, phenylephrine chloride, lipopolysaccharide (from E. coli serotype 026:B6), sodium nitroprusside, isobutyl-methylxanthine, and N -nitro-L-arginine methyl ester hydrochloride were purchased from Sigma Chemical Co. (St. Louis, MO). SNAP was prepared in our laboratory by a published method (Field et al, 1978). Glyceryl trinitrate (Tridil) and heparin were a kind gift of Cristá lia (Sã o Paulo, SP, Brazil).…”

Section: Effect Of N -Nitro-l-arginine Methyl Ester Hydrochloride On mentioning

confidence: 99%

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Fernandes¹,

Silva-Santos²,

Duma³

et al. 2005

Mol Pharmacol

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We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 mol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier.Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.Septic shock, the most severe complication of sepsis, is a serious disorder with significant morbidity and mortality even after the appropriate antibiotic and supportive therapy are initiated. The poor outcome is considered to be a consequence of an overactive systemic inflammatory response elicited by microbial products, mainly lipopolysaccharide. The disease state is characterized by hypotension, hyporeactivity to vasoconstrictor agents, vascular damage and disseminated intravascular coagulation, which leads to multiple organ failure and death (Karima et al., 1999). Because the mortality rate after sepsis is in excess of 50%, it is clear that the present pharmacotherapy is inadequate.Inflammatory stimuli such as lipopolysaccharide activate a pathway that leads to expression, among other proinflammatory proteins, of the inducible nitric-oxide synthase (NOS-2). Once expressed, this enzyme is active for several hours and produces large amounts of nitric oxide (Alderton et al., 2001). It is well established that overproduction of NO in sepsis is one of the main causes of excessive vasodilation and reduced contractile response to vasoconstrictor agents (Titheradge, 1999). Regarding the molecular mechanism of NO-mediated vascular collapse in shock, the role of cGMP-dependent mechanism seems to be well established (Fleming et al., 1991;Paya et al., 1993;Keaney et al., 1994;Silva-Santos et al., 2002). NO activates solu...

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“…SNAP was synthesized by the method of Field et al (1978). SNPL and SNFP were synthesized according to the method of Hart (1985).…”

Section: S-nitrosothiolsmentioning

confidence: 99%

Comparative pharmacology of analogues of S‐nitroso‐N‐acetyl‐dl‐penicillamine on human platelets

Salas

Moro

Askew

et al. 1994

British J Pharmacology

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The effects of two new analogues of S‐nitroso‐N‐acetyl‐dl‐penicillamine (SNAP), S‐nitroso‐N‐formyl‐dl‐penicillamine (SNFP) and S‐nitroso‐dl‐penicillamine (SNPL), on platelet function were examined in vitro. SNAP and its analogues were potent inhibitors of platelet aggregation and inducers of disaggregation. All compounds inhibited fibrinogen binding to platelets. They also decreased the release of P‐selectin from platelets. Both inhibition of fibrinogen binding and release of P‐selectin correlated with an increase in intraplatelet cyclic GMP concentrations. At concentrations sufficient to inhibit platelet function and induce cyclic GMP formation (0.01–3 μm), the release of NO could be detected from SNPL but not from SNAP and SNFP. Release of NO from all compounds was detected at concentrations ≥ 10 μm. Thus, the spontaneous release of NO from SNPL explains the actions of this compound on platelet function; however, platelet‐mediated mechanisms may be involved in the release of NO from SNAP and SNFP.

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ChemInform Abstract: AN UNUSUALLY STABLE THIONITRITE FROM N‐ACETYL‐D,L‐PENICILLAMINE, X‐RAY CRYSTAL AND MOLECULAR STRUCTURE OF 2‐(ACETYLAMINO)‐2‐CARBOXY‐1,1‐DIMETHYLETHYL THIONITRITE

Abstract: Aus den Aminoverbindungen (I) erhält man die Thionitrite (II), von denen (IIa) mit sek. Aminen zu den Nitrosoverbindungen (IV) und mit Methanol oder Natriumborhydrid zu dem Disulfid (V) reagiert.

Cited by 23 publications

References 1 publication

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

Nitric Oxide-Dependent Reduction in Soluble Guanylate Cyclase Functionality Accounts for Early Lipopolysaccharide-Induced Changes in Vascular Reactivity

Comparative pharmacology of analogues of S‐nitroso‐N‐acetyl‐dl‐penicillamine on human platelets

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