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A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system

Miranda, Katrina M., Paolocci, Nazareno, Katori, Tatsuo, Thomas, Douglas D., Ford, Eleonora, Bartberger, Michael D., Espey, Michael G., Kass, David A., Feelisch, Martin, Fukuto, Jon M. and Wink, David A. (2003) A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system Proceedings of the National Academy of Sciences, 100, (16), pp. 9196-9201. (doi:10.1073/pnas.1430507100). (PMID:12865500).

Record type: Article


The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual redox reactions in biological systems. However, several recent studies have demonstrated distinct pharmacological effects for donors of these two species. Here, infusion of the HNO donor Angeli's salt into normal dogs resulted in elevated plasma levels of calcitonin gene-related peptide, whereas neither the NO donor diethylamine/NONOate nor the nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely, plasma cGMP was increased by infusion of diethylamine/NONOate or nitroglycerin but was unaffected by Angeli's salt. These results suggest the existence of two mutually exclusive response pathways that involve stimulated release of discrete signaling agents from HNO and NO. In light of both the observed dichotomy of HNO and NO and the recent determination that, in contrast to the O2/O2- couple, HNO is a weak reductant, the relative reactivity of HNO with common biomolecules was determined. This analysis suggests that under biological conditions, the lifetime of HNO with respect to oxidation to NO, dimerization, or reaction with O2 is much longer than previously assumed. Rather, HNO is predicted to principally undergo addition reactions with thiols and ferric proteins. Calcitonin gene-related peptide release is suggested to occur via altered calcium channel function through binding of HNO to a ferric or thiol site. The orthogonality of HNO and NO may be due to differential reactivity toward metals and thiols and in the cardiovascular system, may ultimately be driven by respective alteration of cAMP and cGMP levels.

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e-pub ahead of print date: 15 July 2003
Published date: 5 August 2003
Keywords: angeli's salt, superoxide dismutase, heme protein, cGMP, calcitonin gene-related peptide
Organisations: Clinical & Experimental Sciences


Local EPrints ID: 337852
ISSN: 0027-8424
PURE UUID: b8412ec6-b7b0-4f42-ae24-d67a27fd6551
ORCID for Martin Feelisch: ORCID iD

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Date deposited: 22 Jun 2012 10:34
Last modified: 18 Jul 2017 06:00

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Author: Katrina M. Miranda
Author: Nazareno Paolocci
Author: Tatsuo Katori
Author: Douglas D. Thomas
Author: Eleonora Ford
Author: Michael D. Bartberger
Author: Michael G. Espey
Author: David A. Kass
Author: Martin Feelisch ORCID iD
Author: Jon M. Fukuto
Author: David A. Wink

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