Effect of nitroxyl on the hamster retinal nitridergic pathway

Sáenz, Daniel A.; Bari, Sara E.; Salido, Ezequiel M; Chianelli, Mónica S.; Rosenstein, Ruth E.

doi:10.1016/j.neuint.2007.04.015

Cited by 6 publications

(8 citation statements)

References 60 publications

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“…Nitroxyl (HNO) has been shown to possess intriguing biological properties. − For instance, HNO has been implicated in the mechanism of the inhibitory effect of cyanamide on aldehyde dehydrogenase in treating alcohol abuse and has been demonstrated to enhance contractility in experimental models of heart failure . That HNO rapidly and irreversibly dimerizes and dehydrates to produce nitrous oxide (eq ), , making it impossible to isolate in pure form, has been a major barrier to achieving a quantitative understanding of its chemical and bioeffector behavior …”

Section: Introductionmentioning

confidence: 99%

Dual Mechanisms of HNO Generation by a Nitroxyl Prodrug of the Diazeniumdiolate (NONOate) Class

et al. 2010

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Here we describe a novel caged form of the highly reactive bioeffector molecule, nitroxyl (HNO). Reacting the labile nitric oxide (NO)- and HNO-generating salt of structure iPrHN−N(O)=NO−Na+ (1, IPA/NO) with BrCH2OAc produced a stable derivative of structure iPrHN-N(O)=NO−CH2OAc (2, AcOM-IPA/NO), which hydrolyzed an order of magnitude more slowly than 1 at pH 7.4 and 37 °C. Hydrolysis of 2 to generate HNO proceeded by at least two mechanisms. In the presence of esterase, straightforward dissociation to acetate, formaldehyde, and 1 was the dominant path. In the absence of enzyme, free 1 was not observed as an intermediate and the ratio of NO to HNO among the products approached zero. To account for this surprising result, we propose a mechanism in which base-induced removal of the N−H proton of 2 leads to acetyl group migration from oxygen to the neighboring nitrogen, followed by cleavage of the resulting rearrangement product to isopropanediazoate ion and the known HNO precursor, CH3−C(O)−NO. The trappable yield of HNO from 2 was significantly enhanced over 1 at physiological pH, in part because the slower rate of hydrolysis for 2 generated a correspondingly lower steady-state concentration of HNO, thus, minimizing self-consumption and enhancing trapping by biological targets such as metmyoglobin and glutathione. Consistent with the chemical trapping efficiency data, micromolar concentrations of prodrug 2 displayed significantly more potent sarcomere shortening effects relative to 1 on ventricular myocytes isolated from wild-type mouse hearts, suggesting that 2 may be a promising lead compound for the development of heart failure therapies.

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Section: Introductionmentioning

confidence: 99%

Dual Mechanisms of HNO Generation by a Nitroxyl Prodrug of the Diazeniumdiolate (NONOate) Class

et al. 2010

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“…Most studies assessed its effects in the cardiovascular system, associated with the oxidation of free cysteine thiol residues [ 30 ], as well as with sarcoplasmic RyRs, increasing calcium release [ 44 ]. A few studies were done in the central nervous system, comparing the effects of AS with the NO• donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) in the hamster retina [ 45 ]. Compared with DEA/NO, AS generates similar inhibition of nNOS activity and L-citrulline transport and reduction of GSH and protein S-nitrosation, but less cGMP induction.…”

Section: Discussionmentioning

confidence: 99%

“…In other models, NAC has been reported to deliver cysteine-cystine increasing GSH in the brain [ 49 ] for long term treatment as needed in neurodegeneration [ 50 ]; however, our results suggest a faster activity that should happen within a 3-h time-window in order to induce circadian resetting through changes in per1–2 activity. In addition, it was shown that the inhibition of the activity of nNOS/cGC/PKGII input pathway components [ 36 , 37 ] delayed the circadian phase, so we could hypothesize that the phase-delays induced by GSH or NAC could be generated by a redox-dependent inhibition of the same pathway, as occurs with NOS activity and L-arginine uptake by AS treatment in the retina [ 45 ]. While Wang et al [ 5 ] evidenced the effect of GSH on resting electrical activity in SCN slices, few circadian studies were done with NAC, which had inconsistent effects [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

et al. 2021

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The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli’s salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.

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“…The precise mechanisms responsible for the effects of HNO and NO on the glutamate/glutamine cycle activity remain to be established. In a previous report, we showed that AS and DEA/NO significantly increases cGMP accumulation in the hamster retina (Sáenz et al, 2007). In order to analyze the involvement of this cyclic nucleotide in the effect of AS and DEA/NO on glutamate/glutamine cycle activity, the effect of two cGMP analogs and a phosphodiesterase inhibitor (IBMX) on glutamate and glutamine uptake, GS and glutaminase activities was examined.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it was demonstrated that AS increases cerebral ischemic damage in mice (Choe et al, 2009). In a previous report, we have shown that HNO and DEA/NO decrease retinal NOS activity, and that HNO decreases L-arginine uptake (Sáenz et al, 2007).…”

Section: Introductionmentioning

confidence: 85%

Effect of Angeli’s salt on the glutamate/glutamine cycle activity and on glutamate excitotoxicity in the hamster retina

Knott

Dorfman

Chianelli

et al. 2012

Neurochemistry International

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Effect of nitroxyl on the hamster retinal nitridergic pathway

Cited by 6 publications

References 60 publications

Dual Mechanisms of HNO Generation by a Nitroxyl Prodrug of the Diazeniumdiolate (NONOate) Class

Dual Mechanisms of HNO Generation by a Nitroxyl Prodrug of the Diazeniumdiolate (NONOate) Class

Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione

Effect of Angeli’s salt on the glutamate/glutamine cycle activity and on glutamate excitotoxicity in the hamster retina

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