Novel substrates for nitric oxide synthases

Xian, Ming; Fujiwara, Noriko; Zhang, Wen; Cai, Tingwei; Kazuma, Satoshi; Jañczuk, Adam; Tang, Xiaoping; Telyatnikov, Vladislav V; Zhang, Yingxin; Chen, Xinchao; Miyamoto, Yasuhide; Taniguchi, Naoyuki; Wang, Peng George

doi:10.1016/s0968-0896(02)00155-4

Cited by 33 publications

(63 citation statements)

References 34 publications

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“…This compound increases L-arginine availability by arginase blockade but does not directly increase NO or citrulline production because it is not a substrate for NOS (16). We chose to utilize this compound because of its low IC 50 and because of the fact that it does not interfere with NOS activity compared with NOHA (16,33). In this study, we demonstrate that inhibition of arginase activity with nor-NOHA restores arginine availability and results in decreased hepatic injury in the liver transplant setting.…”

mentioning

confidence: 83%

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)

Reid¹,

Tsung²,

Kaizu³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liver ischemia-reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. The purpose of this study was to determine whether arginase inhibition with N -hydroxy-nor-L-arginine (nor-NOHA) would increase circulating arginine levels and decrease hepatic damage during liver I/R injury. The effects of nor-NOHA were initially tested in normal animals to determine in vivo toxicity. In the second series of experiments, orthotopic syngeneic liver transplantation (OLT) was performed after 18 h of cold ischemia time in Lewis rats. Animals were given nor-NOHA (100 mg/kg) or saline before and after graft reperfusion. In normal animals treated with nor-NOHA, there were no histopathological changes to organs, liver enzymes, serum creatinine, or body weight. In the OLT model, animals treated with saline exhibited markedly elevated serum transaminases and circulating arginase protein levels. Nor-NOHA administration blunted the increase in serum arginase activity by 80% and preserved serum arginine levels at 3 h after OLT. Nor-NOHA treatment reduced post-OLT serum liver enzyme release by 50%. Liver histology (degree of necrosis) in nor-NOHA-treated animals was markedly improved compared with the saline-treated group. Furthermore, use of the arginase inhibitor nor-NOHA did not influence polyamine synthesis owing to the decrease in ornithine levels. Arginase blockade represents a potentially novel strategy to combat hepatic I/R injury associated with liver transplantation. liver transplantation; arginine; nitric oxide; preservation injury ISCHEMIA-REPERFUSION (I/R) injury is a pathophysiological process whereby hypoxic organ damage is accentuated following return of blood flow and oxygen delivery to the compromised tissue. Transient episodes of hepatic ischemia occur during solid organ transplantation, trauma, hypovolemic shock, and elective liver resection, when inflow occlusion or total vascular exclusion is used to minimize blood loss. The pathophysiology of liver I/R injury includes both direct cellular damage as the result of the ischemic insult as well as delayed dysfunction and damage resulting from activation of inflammatory pathways (3,6,8,21,26,29). The injury that results from I/R after liver transplantation contributes to primary nonfunction in ϳ5-10% of liver grafts and delayed graft function in 15-30% of cases (9, 30).Nitric oxide (NO) is known to have an important role in regulating liver physiology and blood flow. NO and citrulline are produced by the family of nitric oxide synthases (NOS) from the substrate L-arginine (32). NO has been shown to exert protective effects in the liver by improving blood flow, antagonizing neutrophil activation and adhesion, neutralizing free radical injury, and eliciting antiapoptotic effects (19, 23). The beneficial effects of the L-arginine-NO pathway have also been reported in liver transplantation models. Experiments using arginine supplementation and NO donors have shown that NO serves to improve liver ischemia injury...

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mentioning

confidence: 83%

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)

Reid¹,

Tsung²,

Kaizu³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…4a) [6]. It has been successfully employed in previous work and was shown to be a reliable pathway for the preparation of primary and secondary N-hydroxyguanidines including NOHA, homo-NOHA and nor-NOHA [9][10][11][12][13]. The second method involves isothioureas as a key intermediate [6,14] (Fig.…”

Section: Ii2 Synthesis Of N-hydroxyguanidinesmentioning

confidence: 99%

“…Based on this hypothesis, Wang's group has synthesized a series of compounds bearing a N-hydroxyguanidine functional group and studied their oxidation by recombinant NOSs [9]. Interestingly, it was found that some N-alkyl-N'-hydroxyguanidines are good substrates for NOSs.…”

Section: N-alkyl-n'-hydroxyguanidines As Nos Substratesmentioning

confidence: 99%

“…Since some N-alkyl-N'-hydroxyguanidines were found to be good substrates of NOSs, a series of N-aryl-N'-hydroxyguanidines were also synthesized and studied for their oxidation by purified recombinant NOSs [9,11,66]. Very interestingly, some of these compounds were shown not only to be good substrates of NOS, but also have good selectivity for iNOS.…”

Section: As Selective Substrates Of Nosmentioning

confidence: 99%

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N-Hydroxyguanidines as Substrates of Nitric Oxide Synthases

Cai¹,

Lu²,

Wang³

2005

CTMC

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Nitric oxide (NO) has been implicated in a wide variety of disease states. Both inhibitors and substrates of nitric oxide synthase (NOS) could have great therapeutic potential in the treatment of these diseases. There is considerable pharmacological interest in developing inhibitors of NOS, and hundreds of inhibitors have been identified. In contrast, the study on NOS substrates is less active. The advances in the identification, design and development of NOS substrates are discussed in this review. The focus is the chemistry and biochemistry of N-hydroxyguanidines. The crystal structures of substrates bound to NOSs and the mechanisms of NOS catalyzed NO generation from substrates are also discussed.

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“…The cyanamides 2a-m were reported and fully characterized by spectroscopic methods. [22][23][24][25][26][27][28][29][30][31][32] For example, compound 2k possessed characteristic peak at 123.72 ppm, which represented the 13 C in NH-C"N. The IR absorptions of 2k showed peaks at 2226 cm À1 for stretching of the -C"N group and at 3365 cm À1 for stretching of the -NH group.…”

Section: Introductionmentioning

confidence: 99%

Desulfurization and transformation of isothiocyanates to cyanamides by using sodium bis(trimethylsilyl)amide

Chen

Wong

Huang

et al. 2008

Tetrahedron Letters

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Novel substrates for nitric oxide synthases

Cited by 33 publications

References 34 publications

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)

N-Hydroxyguanidines as Substrates of Nitric Oxide Synthases

Desulfurization and transformation of isothiocyanates to cyanamides by using sodium bis(trimethylsilyl)amide

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Novel substrates for nitric oxide synthases

Cited by 33 publications

References 34 publications

Liver I/R injury is improved by the arginase inhibitor, Nω-hydroxy-nor-l-arginine (nor-NOHA)

Liver I/R injury is improved by the arginase inhibitor, Nω-hydroxy-nor-l-arginine (nor-NOHA)

N-Hydroxyguanidines as Substrates of Nitric Oxide Synthases

Desulfurization and transformation of isothiocyanates to cyanamides by using sodium bis(trimethylsilyl)amide

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About

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)

Liver I/R injury is improved by the arginase inhibitor, N^ω-hydroxy-nor-l-arginine (nor-NOHA)