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
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.
Available from: Jenna Dumond
- "Moreover , HNO possesses antithrombotic properties (Mondoro et al., 2001; Bermejo et al., 2005), is resistant to scavenging by superoxide (Miranda et al., 2002, 2003b; Switzer et al., 2009), and causes a reduction of blood pressure in vivo (Ma et al., 1999; Choe et al., 2009). The mechanisms of HNO-induced increases in myocardial contractility have been well investigated (Cheong et al., 2005; Dai et al., 2007; Tocchetti et al., 2007, 2011; Froehlich et al., 2008; Gao et al., 2012) as has the mechanism of HNO-induced vasorelaxation in small resistance arteries (Irvine et al., 2003; Coleman et al., 2006; Andrews et al., 2009; Favaloro and Kemp-Harper, 2009; Bullen et al., 2011a,b). In contrast, the mechanism of how HNO elicits vasorelaxation in large arteries needs further investigation. "
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ABSTRACT: Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases. 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classical HNO donors Angeli's salt and isopropylamine NONOate predominantly releases HNO and has a longer half-life. This study investigated the vasodilatative properties of NCA in isolated aortic rings, human platelets, and its mechanism of action. NCA was applied on aortic rings isolated from wild-type mice, apolipoprotein E-deficient mice and in endothelial-denuded aorta. The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger GSH and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP) and K+ channels. NCA induced a concentration dependent relaxation (EC50 4.4 µM). This response did not differ between all groups indicating an endothelium-independent relaxation effect. The concentration-response was markedly decreased in presence of excess GSH; while the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide had no effect. Inhibitors of sGC, CGRP, and voltage-dependent K+ channel each significantly impaired the vasodilatator response to NCA. In contrast, inhibitors of AC, ATP-sensitive K+ channel or high conductance Ca2+-activated K+ channel did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by thromboxane A2 mimetic U-46619 in a cGMP dependent manner. In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation.
Available from: Owen Woodman
- "Like NO, HNO has the ability to cause vascular relaxation via the generation of cGMP but HNO has additional, distinct pharmacological actions in comparison to NO . For example, Miranda et al. (2002) demonstrated that, unlike NO the HNO donor Angeli's salt does not react with superoxide anions to form peroxynitrite , suggesting that HNO-mediated vasodilatation could be preserved under oxidative stress conditions. "
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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.
Available from: Isra Marei
- "(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.
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