Characterization of cell selectivity of two novel inhibitors of nitric oxide synthesis

Lambert, Laurie E.; French, John F.; Whitten, Jeffrey P.; Baron, Bruce M.; McDonald, Ian A.

doi:10.1016/0014-2999(92)90221-o

Cited by 52 publications

(14 citation statements)

References 7 publications

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“…This is supported by the finding that treatment with inhibitors of NOS, such as the L-arginine analogues N G -cyclopropyl-L-arginine, N G -methyl-L-arginine, N G -nitro-L-arginine and its methyl ester (Gross et al 1990(Gross et al , 1991Lambert et al 1991Lambert et al , 1992, as well as the S-substituted isothioureas (Southan et al 1995;Szabò et al 1994), increases survival time and rate and improves blood pressure in haemorrhagic, septic and splanchnic artery occlusion shock, and protects against cellular damage and multiple organ dysfunction induced by the experimental hypoxic conditions (Bazzani et al 1997;Katchman and Hershkowitz 1997;Nowicki et al 1991;Squadrito et al 1994;Szabò et al 1994;Thiemermann et al 1993;Yao et al 1996;Zingarelli et al 1992).…”

Section: Introductionsupporting

confidence: 55%

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

Bazzani¹,

Bini

Cainazzo

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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Anaesthetized rats, endotracheally intubated and mechanically ventilated with room air, were subjected to a 5-min period of asphyxia by turning off the ventilator. The ventilator was then turned back on and, simultaneously, the animals were treated with either the adrenocorticotropin fragment 1-24 [ACTH-(1-24), 160 microg/kg in a volume of 1 ml/kg i.v.] or an equivalent volume of saline. Nitric oxide (NO)-haemoglobin formation was detected ex vivo in arterial blood by electron spin resonance spectrometry; arterial blood pressure, electrocardiogram (ECG) and electroencephalogram (EEG) were monitored for a 60-min observation period, or until prior death. During asphyxia, there was massive formation of NO (red cell concentrations 40-80 microM), associated with a dramatic fall in mean arterial pressure and pulse pressure, marked bradycardia and ECG signs of ischaemic damage, as well as an isoelectric EEG. Treatment with ACTH-(1-24) produced a prompt (within 15 min) and long-lasting drop in NO blood levels, associated with an almost immediate (within 1 min) restoration of cardiovascular function and with a more gradual recovery of EEG, which became normal after 3040 min; all parameters remained stable throughout the 60-min observation period. In saline-treated rats, on the other hand, there was a further increase in NO blood levels, as detected 3 min after treatment, and all died within 5-8 min. Moreover, pretreatment and treatment with S-methylisothiourea sulphate (SMT, 3 mg/kg i.v.), a relatively specific inhibitor of inducible NO synthase, inhibited NO formation, but did not affect the mortality rate (100% within 5-8 min). The present results provide the first evidence that prolonged asphyxia is associated with high blood concentrations of NO, and that the life-saving effect of melanocortin peptides in severe hypoxic conditions is associated with a complete normalization of NO blood levels. However, the lack of SMT protection in this experimental model seems to rule out the possibility that the ACTH-(1-24)-induced resuscitation is due to an effect on NO overproduction.

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Section: Introductionsupporting

confidence: 55%

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

Bazzani¹,

Bini

Cainazzo

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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“…In this context it has been shown that hArg can serve exclusively as a substrate for NOS in macrophages [43]. Interestingly, the pharmacological transformation of hArg to the NOS inhibitor NH2-homoarginine results in significantly decreased NO production by macrophages [44]. One may speculate that decreased hArg levels may indicate monocyte “anergy” and this may explain why the hArg:ADMA ratio may be better than the lArg:ADMA ratio for diagnosing sepsis severity.…”

Section: Discussionmentioning

confidence: 99%

Markers of nitric oxide are associated with sepsis severity: an observational study

et al. 2017

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BackgroundNitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity.MethodThis single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression.ResultslArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30–2.29) μmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36–1.44) μmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46–0.65) μmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56–1.39) μmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA.ConclusionsIn patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.

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“…An extensive range of related guanidino-Nsubstituted arginine (and homoarginine) analogues has since been prepared and many are claimed to have inhibitory activity against the NOS isoforms [82][83][84][85]. Compounds (4) to (10) are representative of those described.…”

Section: L-arginine Analoguesmentioning

confidence: 97%

Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?

Tinker¹,

Wallace²

2006

CTMC

103

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Nitric Oxide (NO) is widely recognized as an important messenger and effector molecule in a variety of biological systems. There is strong evidence from animal models that elevated or lowered NO levels are associated with a variety of pathological states. In nature, NO is synthesised from the amino acid l-arginine by a small family of closely related oxygenase enzymes: the nitric oxide synthases (NOS). A number of studies in animals have associated excessive NO production by one of these enzymes--the inducible NOS isoform (iNOS or NOS-II)--with acute and chronic inflammation in model systems and have also demonstrated that administration of NOS inhibitors can produce beneficial effects. Regrettably, however, the relatively poor potency, selectivity and pharmacokinetic (ADME) profiles of the available inhibitors have so far precluded a convincing demonstration of their efficacy in the clinic. This review will describe the current state of knowledge of the structure and function of NOS and the various approaches that are being followed in the search for truly selective NOS inhibitors as therapeutic agents for inflammatory diseases.

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Characterization of cell selectivity of two novel inhibitors of nitric oxide synthesis

Cited by 52 publications

References 7 publications

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

High blood levels of nitric oxide in rats subjected to prolonged respiratory arrest and their modulation during adrenocorticotropin-induced resuscitation

Markers of nitric oxide are associated with sepsis severity: an observational study

Selective Inhibitors of Inducible Nitric Oxide Synthase: Potential Agents for the Treatment of Inflammatory Diseases?

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