Nitroxyl (HNO) as a Vasoprotective Signaling Molecule

Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 05/2011; 14(9):1675-86. DOI: 10.1089/ars.2010.3327
Source: PubMed


Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO(•)), is rapidly emerging as a novel nitrogen oxide with distinct pharmacology and therapeutic advantages over its redox sibling. Whilst the cardioprotective effects of HNO in heart failure have been established, it is apparent that HNO may also confer a number of vasoprotective properties. Like NO(•), HNO induces vasodilatation, inhibits platelet aggregation, and limits vascular smooth muscle cell proliferation. In addition, HNO can be putatively generated within the vasculature, and recent evidence suggests it also serves as an endothelium-derived relaxing factor (EDRF). Significantly, HNO targets signaling pathways distinct from NO(•) with an ability to activate K(V) and K(ATP) channels in resistance arteries, cause coronary vasodilatation in part via release of calcitonin-gene related peptide (CGRP), and exhibits resistance to scavenging by superoxide and vascular tolerance development. As such, HNO synthesis and bioavailability may be preserved and/or enhanced during disease states, in particular those associated with oxidative stress. Moreover, it may compensate, in part, for a loss of NO(•) signaling. Here we explore the vasoprotective actions of HNO and discuss the therapeutic potential of HNO donors in the treatment of vascular dysfunction.

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    • "4.3. Role of NO and HNO-mediated relaxation in the presence of superoxide anions Despite reports suggesting that HNO has distinct pharmacological actions and therapeutic advantages over NO, including having little or no reactivity with superoxide anions [5] [13], some doubt remains as to whether HNO-induced relaxation is affected by oxidant stress [14] [15]. In this study, we demonstrated that vascular relaxation to the NO donor DEA is significantly attenuated by the presence of superoxide anions, whereas relaxation to the HNO donor AS was not affected by pyrogallol. "
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    ABSTRACT: The aim of the study was to investigate whether diabetes-induced oxidant stress affects the contribution of nitroxyl (HNO) to endothelium-dependent relaxation in the rat aorta. Organ bath techniques were employed to determine vascular function of rat aorta. Pharmacological tools (3mM l-cysteine, 5mM 4-aminopyridine (4-AP), 200μM carboxy-PTIO and 100μM hydroxocobalamin, HXC) were used to distinguish between NO and HNO-mediated relaxation. Superoxide anion levels were determined by lucigenin-enhanced chemiluminescence. In the diabetic aorta, where there is increased superoxide anion production, responses to the endothelium-dependent relaxant ACh were not affected when the contribution of NO to relaxation was abolished by either HXC or carboxy-PTIO, indicating a preserved HNO-mediated relaxation. Conversely, when the contribution of HNO was inhibited with l-cysteine or 4-AP, the sensitivity and maximum relaxation to ACh was significantly decreased, suggesting that the contribution of NO was impaired by diabetes. Furthermore, whereas HNO appears to be derived from eNOS in normal aorta, in the diabetic aorta it may also arise from an eNOS-independent source, perhaps derived from nitrosothiol stores. Similarly, exposure to the superoxide anion generator, pyrogallol (100μM) significantly reduced the sensitivity to the NO donor, DEANONOate and ACh-induced NO-mediated relaxation but had no effect on responses to the HNO donor, Angeli's salt and ACh-induced HNO-mediated relaxation in the rat aorta. These findings demonstrate that NO-mediated relaxation is impaired during oxidative stress but the HNO component of relaxation is preserved under those conditions.
    Pharmacological Research 08/2012; 66(5):383-91. DOI:10.1016/j.phrs.2012.07.010 · 4.41 Impact Factor
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    • "(Akaike et al. 1993; Wanstall et al. 2001). The contribution of the one electron reduced nitroxyl form of NO, HNO, or, more accurately named, nitrosyl hydride or hydrogen oxynitrate , to biological function has also been recognised (Li et al. 1999; Bullen et al. 2011; Fukuto and Carrington 2011; Kemp-Harper 2011; Tocchetti et al. 2011). HNO has physiological targets and actions that, at least partially, distinguish it from NO • , including cardiac and vasoprotection as well as a role in nitrergic transmission (Li et al. 1999; Lundberg et al. 2005; Bullen et al. 2011; Fukuto and Carrington 2011; Kemp-Harper 2011; Tocchetti et al. 2011). "
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    ABSTRACT: The endothelium, although only a single layer of cells lining the vascular and lymphatic systems, contributes in multiple ways to vascular homeostasis. Subsequent to the 1980 report by Robert Furchgott and John Zawadzki, there has been a phenomenal increase in our knowledge concerning the signalling molecules and pathways that regulate endothelial - vascular smooth muscle communication. It is now recognised that the endothelium is not only an important source of nitric oxide (NO), but also numerous other signalling molecules, including the putative endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI(2)), and hydrogen peroxide (H(2)O(2)), which have both vasodilator and vasoconstrictor properties. In addition, the endothelium, either via transferred chemical mediators, such as NO and PGI(2), and (or) low-resistance electrical coupling through myoendothelial gap junctions, modulates flow-mediated vasodilatation as well as influencing mitogenic activity, platelet aggregation, and neutrophil adhesion. Disruption of endothelial function is an early indicator of the development of vascular disease, and thus an important area for further research and identification of potentially new therapeutic targets. This review focuses on the signalling pathways that regulate endothelial - vascular smooth muscle communication and the mechanisms that initiate endothelial dysfunction, particularly with respect to diabetic vascular disease.
    Canadian Journal of Physiology and Pharmacology 05/2012; 90(6):713-38. DOI:10.1139/y2012-073 · 1.77 Impact Factor
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    ABSTRACT: Nitroxyl (HNO), the one electron reduced and protonated congener of nitric oxide, is emerging as a novel nitrogen oxide with distinct chemistry and biological actions as compared with its redox sibling. The "thiophilic" nature of HNO underlies many of its unique properties, and attention has been focused on its regulation of cellular function and therapeutic potential, particularly in the treatment of cardiovascular disease. The present Forum issue summarizes the intriguing chemistry and biology of HNO and highlights its impact in the cardiovascular and central nervous systems. Recent advances in the development of new HNO donors and their potential use as tools to study HNO signaling and therapeutic agents are discussed. Evidence is also provided for a role of HNO as a putative, endogenous regulator of vascular function. However, as highlighted in this Forum issue, the development of sensitive methods for HNO detection in a biological system is needed to conclusively prove its in vivo generation. As research expands in this area, it is likely that new targets and pharmacological applications of HNO will be discovered.
    Antioxidants & Redox Signaling 02/2011; 14(9):1609-13. DOI:10.1089/ars.2011.3937 · 7.41 Impact Factor
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