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. 2003 Aug 5;100(16):9196-201.
doi: 10.1073/pnas.1430507100. Epub 2003 Jul 15.

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

Katrina M Miranda  1 , Nazareno Paolocci, Tatsuo Katori, Douglas D Thomas, Eleonora Ford, Michael D Bartberger, Michael G Espey, David A Kass, Martin Feelisch, Jon M Fukuto, David A Wink
Affiliations

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

Katrina M Miranda et al. Proc Natl Acad Sci U S A. .

Abstract

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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Figures

Fig. 1.
Fig. 1.
Oxidation of ferricyt c by AS. (A) Effect of constant AS (5 μM final) and varied ferricyt c (2–100 μM). (B) Effect of varied AS (5–200 μM) and constant ferricyt c (100 μM).
Fig. 2.
Fig. 2.
Oxidation of DHR by AS. (A) Varied amounts of AS (0.5–50 μM final) were added to assay buffer containing DHR (25 μM). (B) Aliquots of AS (0.5 μM final) were added to assay buffer containing DHR (25 μM) and varying amounts of GSH, NAC, CuZnSOD (all 0.5–8 μM), or catalase (0.5-5 μM).
Scheme 1.
Scheme 1.
See this image and copyright information in PMC

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