Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

Miao, Zhengrui; King, S. Bruce

doi:10.1016/j.niox.2016.04.006

Cited by 72 publications

(39 citation statements)

References 158 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nitroxyl (azanone, HNO) is a highly reactive protonated • NO congener that has been reported due to its distinct redox chemical and biological properties. Interestingly, many of the properties attributed to • NO may in fact be mediated by HNO . Although HNO can be putatively generated by NOS‐dependent and independent sources, its endogenous generation remains poorly understood due to its fast dimerization to nitrous oxide ( 1 HNO → 3 NO − + N 2 O, k dim = 8 × 10 6 M −1 ·s −1 ) …”

Section: Introductionmentioning

confidence: 99%

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

Oliveira

Benfeito

Fernandes

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

The biological effects attributed to nitric oxide ( NO) and nitroxyl (HNO) have been extensively studied, propelling their array of putative clinical applications beyond cardiovascular disorders toward other age-related diseases, like cancer and neurodegenerative diseases. In this context, the unique properties and reactivity of the N-O bond enabled the development of several classes of compounds with potential clinical interest, among which NO and HNO donors, nitrones, and nitroxides are of particular importance. Although primarily studied for their application as cardioprotective agents and/or molecular probes for radical detection, continuous efforts have unveiled a wide range of pharmacological activities and, ultimately, therapeutic applications. These efforts are of particular significance for diseases in which oxidative stress plays a key pathogenic role, as shown by a growing volume of in vitro and in vivo preclinical data. Although in its early stages, these efforts may provide valuable guidelines for the development of new and effective N-O-based drugs for age-related disorders. In this report, we review recent advances in the chemistry of NO and HNO donors, nitrones, and nitroxides and discuss its pharmacological significance and potential therapeutic application.

show abstract

Section: Introductionmentioning

confidence: 99%

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

Oliveira

Benfeito

Fernandes

et al. 2017

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…There has been considerable research regarding the one electron reduced congener of nitric oxide (NO), nitroxyl anion (NO − ) (Irvine et al , 2003; Favaloro & Kemp-Harper, 2007; Irvine et al , 2007; Irvine et al , 2008; Andrews et al , 2009; Chin et al , 2016; Miao & King, 2016; Shoman & Aly, 2016). It was previously thought that NO − exists as an anion (pKa 4.7) at a physiological pH; however, this assumption was corrected in 2002, when investigators determined the actual pKa to be around 11.4.…”

Section: Introductionmentioning

confidence: 99%

Angeli's Salt, a nitroxyl anion donor, reverses endothelin-1 mediated vascular dysfunction in murine aorta

Wynne

Labazi

Carneiro

et al. 2017

European Journal of Pharmacology

View full text Add to dashboard Cite

Nitroglycerin (Gtn) is a treatment for cardiovascular patients due to its vasodilatory actions, but induces tolerance when given chronically. A proposed mechanism is the superoxide (O2−)oxidative stress hypothesis, which suggests that Gtn increases O2− production. Nitric oxide (NO) exists in three different redox states; the protonated, reduced state, nitroxyl anion (HNO) is an emerging candidate in vascular regulation. HNO is resistant to scavenging and of particular interest in conditions where high levels of reactive oxygen species (ROS) exist. We hypothesize that treatment with Gtn will exacerbate endothelin 1 ( ET-1) induced vascular dysfunction via an increase in ROS, while treatment with Angeli’s Salt (AS), an HNO donor, will not. Aorta from mice were isolated and divided into four groups: vehicle, ET-1 [0.1μM, 1μM], ET-1+Gtn [Gtn 1μM] and ET-1+AS [AS 1μM]. Concentration response curves (CRCs) to acetylcholine (ACh) and phenylephrine (Phe) were performed. Aorta incubated with ET-1 (for 20–22hrs) exhibited a decreased relaxation response to ACh and an increase in Phe-mediated contraction. Aorta incubated with AS exhibited a reversal in ET-1 induced vascular and endothelial dysfunction. ET-1 increased ROS in aortic vascular smooth muscle cells (VSMCs), visualized by dihydroethidium (DHE) staining. AS incubated reduced this ROS generation, yet maintained with Gtn treatment. These data suggest that aorta incubated with the HNO donor, AS, can reverse ET-1 mediated vascular dysfunction, which may be through a decrease or prevention of ROS generation. We propose that HNO may be vasoprotective and that HNO donors studied as a therapeutic option where other organic nitrates are contraindicative.

show abstract

“…[18] Intriguingly,c ellular generation of HNO from the reaction between H 2 Sa nd NO has been implicated in regulating vascular tone and blood flow through an HNO/ TRPA1/CGRP pathway. [20] HNO detection is complicated by its rapid dimerization and elimination to form nitrous oxide (N 2 O). [20] HNO detection is complicated by its rapid dimerization and elimination to form nitrous oxide (N 2 O).…”

mentioning

confidence: 99%

A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

Ryan

Reeves

et al. 2018

Angewandte Chemie

View full text Add to dashboard Cite

Azanone (HNO) is ar eactive nitrogen species with pronounced biological activity and high therapeutic potential for cardiovascular dysfunction. Ac ritical barrier to understanding the biology of HNO and furthering clinical development is the quantification and real-time monitoring of its delivery in living systems.H erein, we describe the design and synthesis of the first chemiluminescent probe for HNO, HNOCL-1,w hich can detect HNO generated from concentrations of Angeliss alt as lowa s1 38 nm with high selectivity based on the reaction with ap hosphine group to form as elfcleavable azaylide intermediate.W eh ave capitalized on this high sensitivity to develop ag eneralizable kinetics-based approach,whichprovides real-time quantitative measurements of HNO concentration at the picomolar level. HNOCL-1 can monitor dynamics of HNO delivery in living cells and tissues, demonstrating the versatility of this method for tracking HNO in living systems.Azanone (HNO,n itroxyl), is chemically related to nitric oxide (NO) by the addition of one electron and one proton. HNO rapidly dimerizes and eliminates to form nitrous oxide (k = 8 10 6 m À1 s À1 at 23 8 8C) [1] and reacts with molecular oxygen with estimated rate constants that range from 10 3 to 10 4 m À1 s À1 (k = 3 10 3 m À1 s À1 at 37 8 8C; [2] k = 1 10 4 m À1 s À1 at 23 8 8C; [3] k = 1.8 10 4 m À1 s À1 at 25 8 8C [4,5] ). Tw omajor biological targets responsible for HNO bioactivity are thiols,which react directly with HNO to form sulfinamides (k = 2 10 6 m À1 s À1 at 37 8 8C) [2] and the iron in heme-containing proteins. [6] While both HNO and NO can activate soluble guanylyl cyclase,only HNO acts apositive cardiac inotrope by direct reaction with cysteine residues on cardiac ryanodine receptors and the sarcoplasmic reticulum Ca 2+

show abstract

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

Cited by 72 publications

References 158 publications

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

Angeli's Salt, a nitroxyl anion donor, reverses endothelin-1 mediated vascular dysfunction in murine aorta

A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

Contact Info

Product

Resources

About