Inhibition of nitric oxide formation by guanidines

Hasan, Khalid; Heesen, B J; Corbett, John A.; McDaniel, Michael L.; Chang, Katherine; Allison, Wanda; Wolffenbuttel, Bruce H. R.; Williamson, Joseph R.; Tilton, Ronald G.

doi:10.1016/0014-2999(93)90667-7

Cited by 152 publications

(63 citation statements)

References 17 publications

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“…Hasan et al [50] have demonstrated that AG is a selective inhibitor of iNOS in the rat beta-cell insulinoma cell line RINm5F and also in isolated pancreatic islets. The effects of AG on blood flow and vascular albumin permeability in diabetic rats have been shown to be restricted to tissues undergoing diabetic vascular injury [51].…”

Section: Discussionmentioning

confidence: 99%

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats

et al. 1997

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The process of advanced glycation leads to irreversible cross-linking of long-lived proteins [1]. This process is accentuated in diabetes and has been postulated to contribute to the development of a range of diabetic complications including nephropathy [2], retinopathy [3] and neuropathy [4]. Aminoguanidine (AG) has previously been shown to retard the development of advanced glycation end products (AGEs) in various tissues in streptozotocin diabetes [5]. In those studies, AG was shown to decrease mesangial expansion and albuminuria, both markers of the

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Section: Discussionmentioning

confidence: 99%

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats

et al. 1997

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“…Thus, it is conceivable that pharmacological NO synthase inhibitors will affect both isoforms of the enzyme, confounding the experimental data obtained. Moreover, some of the analogs used to inhibit iNOS activity, such as aminoguanidine (16,17), may directly interfere with ␤-cell function (18)(19)(20), making it difficult to evaluate their potential impact on cytokine-induced ␤-cell dysfunction.…”

Section: Cytokines Induce Apoptosis In ␤-Cellsmentioning

confidence: 99%

Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-).

et al. 2000

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Prolonged exposure of rodent ␤-cells to combinations of cytokines induces the inducible form of nitric oxide synthase (iNOS) expression and Fas expression, nitric oxide (NO) production, and cell death. It also induces the expression of potential "defense" genes, such as manganese superoxide dismutase (MnSOD) and heat shock protein (hsp) 70. NO is a radical with multifaceted actions. Recent studies have shown that NO, in addition to having cytotoxic actions, may regulate gene transcription. It remains unclear whether NO mediates cytokine-induced gene expression and subsequent ␤-cell death. Previous studies using NO synthase blockers yielded conflicting results, which may be due to nonspecific effects of these agents. In this study, we examined the effects of cytokines on gene expression, determined by reverse transcriptase-polymerase chain reaction (RT-PCR), and viability, determined by nuclear dyes, of pancreatic islets or fluorescence-activated cell sorter (FACS)-purified ␤-cells isolated from iNOS knockout mice (iNOS -/ -, background C57BL/6x129SvEv) or their respective controls (C57BL/6x129SvEv). The combination of cytokines used was interleukin-1␤ (50 U/ml) plus ␥-interferon (1,000 U/ml) plus tumor necrosis factor-␣ (1,000 U/ml). The lack of cytokine-induced iNOS activity in the iNOS -/-islet cells was confirmed by RT-PCR and nitrite determination. Cytokines induced a >3-fold increase in Fas and MnSOD mRNA expression in wild-type (WT) and iNOS -/-islets. On the other hand, hsp 70 was induced in WT but not in iNOS -/-islets. Prolonged (6-9 days) exposure of WT islets to cytokines leads to an 80-90% decrease in islet cell viability, whereas viability decreased by only 10-30% in iNOS -/-islet cells. To determine the mode of cytokine-induced cell death, FACS-purified ␤-cells were exposed to the same cytokines. After 9 days, the apoptosis index was similarly increased in WT (39 ± 3%) and iNOS -/-(33 ± 4%) ␤-cells. On the other hand, cytokines increased necrosis in WT (20 ± 4%) but not in iNOS -/-(7 ± 3%) ␤-cells. From these data, we concluded that 1) NO is required for cytokine-induced hsp 70 mRNA expression but not for Fas and MnSOD expression, 2) cytokines induce both apoptosis and necrosis in mouse ␤-cells, and 3) cytokine-induced apoptosis is mostly NO-independent, whereas necrosis requires NO formation. Diabetes

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“…But, the most commonly used inhibitors of NOS, namely N G -monomethyl-L-arginine (L-NMMA), N G -nitro-L-arginine (L-NA) and its methyl ester (L-NAME), inhibits eNOS at least as strongly as they inhibit iNOS (Gross et al, 1991). Non-amino acid analogues of L-arginine such as aminoguanidine (Misako et al, 1993), alkylguanidines (Hansan et al, 1993) and Salkylisothiourea (Garvey et al, 1994) have also been reported to inhibit NOS. These compounds show some selectivity for iNOS.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of human inducible nitric oxide synthase by S‐alkyl‐L‐isothiocitrulline‐containing dipeptides

Park

Higuchi

Kikuchi

et al. 2001

British J Pharmacology

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1 The aim of this study was to investigate the structure-activity relationship of S-alkyl-Lisothiocitrulline-containing dipeptides towards three partially puri®ed recombinant human nitric oxide synthase (NOS) isozymes, as well as the e ects of these compounds on cytokine-induced NO production by human DLD-1 cells. 2 In an in vitro assay, S-methyl-L-isothiocitrulline (L-MIT) was slightly selective for human neuronal NOS (nNOS) over the inducible (iNOS) or endothelial (eNOS) isozyme, but the combination of a hydrophobic L-amino acid (L-Phe, L-Leu or L-Trp) with L-MIT dramatically altered the inhibition pattern to give selective iNOS inhibitors. Introduction of a hydroxy, nitro, amino or methoxy group at the para position of the aromatic ring of L-MIT-L-Phe (MILF) decreased the selectivity and inhibitory potency. A longer or larger S-alkyl group also decreased the selectivity and potency. Dixon analysis showed that all of the dipeptides were competitive inhibitors of the three isoforms of human NOS. The enzymatic time course curves indicated that MILF was a slow binding inhibitor of human iNOS. 3 These results suggest that the human NOS isozymes have di erent-sized cavities in the binding site near the position to which the C-terminal of L-arginine binds, and the cavity of iNOS is hydrophobic. Interestingly, L-MIT-D-Phe (MIDF) showed little inhibitory activity or selectivity, suggesting that the cavity of human iNOS is located in a well-de®ned direction from the a carbon atom. 4 NO production in cytokine-stimulated human DLD-1 cells was measured with a¯uorescent indicator, DAF-FM. MILF, L-MIT-L-Trp(-CHO) (MILW) and L-MIT-L-Tyr (MILY) showed more potent activity than L-MIT in this whole-cell assay. 5 Thus, S-alkyl-L-isothiocitrulline-containing dipeptides are selective inhibitors of human iNOS, and work e ciently in cell-based assay.

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Inhibition of nitric oxide formation by guanidines

Cited by 152 publications

References 17 publications

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats

Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats

Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-).

Selective inhibition of human inducible nitric oxide synthase by S‐alkyl‐L‐isothiocitrulline‐containing dipeptides

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