Nitroxyl gets to the heart of the matter

Louisiana State University Health Sciences Center, Department of Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA 71130, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2003; 100(9):4978-80. DOI: 10.1073/pnas.1031571100
Source: PubMed
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    • "There is considerable interest in this redox variant of NO, since there is mounting evidence that HNO acts via a pharmacological pathway that is distinct from NO U ; an intriguing concept with the potential to give rise to a new class of vasodilator agents. Indeed, the potential advantage of HNO over NO U donors in heart failure has been documented [19]. "
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    ABSTRACT: The nitroxyl anion (HNO) is the one-electron reduction product of NO(). This redox variant has been shown to be endogenously produced and to have effects that are pharmacologically distinct from NO(). This study investigates the vasodilator and chronotropic effects of HNO in the rat isolated coronary vasculature. Sprague-Dawley rat hearts were retrogradely perfused with Krebs' solution (8 ml/min) using the Langendorff technique. Perfusion pressure was raised using a combination of infusion of phenylephrine and bolus additions of the thromboxane mimetic U46619 to attain a baseline perfusion pressure of 100-120 mm Hg. The vasodilator effects of a nitroxyl anion donor, Angeli's salt, were examined in the absence and presence of HNO and NO* scavengers, K+ channel inhibition, and soluble guanylate cyclase (sGC) inhibition. In addition, the inotropic and chronotropic effects of Angeli's salt were examined in hearts at resting perfusion pressure (50-60 mm Hg) and compared to responses evoked by acetylcholine and isoprenaline. Angeli's salt causes a potent and reproducible vasodilatation in isolated perfused rat hearts. This response is unaffected by the NO* scavenger hydroxocobalamin (0.1 mM) but is significantly inhibited by the HNO scavenger N-acetyl-L-cysteine (4 mM), suggesting that HNO is the mediator of the observed responses. Vasodilatation responses to Angeli's salt were virtually abolished in the presence of the sGC inhibitor ODQ (10 microM). The magnitude of the vasodilatation response to Angeli's salt was significantly reduced in the presence of 30 mM K+, 10 microM glibenclamide and in the presence of the calcitonin gene-related peptide (CGRP) antagonist CGRP((8-37)) (0.1 microM). Angeli's salt had little effect on heart rate or force of contraction, whilst isoprenaline and acetylcholine elicited significant positive and negative cardiotropic effects, respectively. The HNO donor Angeli's salt elicits a potent and reproducible vasodilatation response. The results suggest that the response is elicited by HNO through sGC-mediated CGRP release and K(ATP) channel activation.
    Cardiovascular Research 03/2007; 73(3):587-96. DOI:10.1016/j.cardiores.2006.11.018 · 5.94 Impact Factor
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    • "Likewise, it was demonstrated that nitroxyl might exert deleterious cardiovascular effects as well [41]. It was suggested that HNO/NO À involved in these processes in vivo might be generated directly from NOS activity or from decomposition of S-nitrosothiols [10] [38]. Microvascular endothelium is a major site of production of urate in the coronary system and there is a net release of urate from human myocardium [42]. "
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    ABSTRACT: The conversion of NO into its congeners, nitrosonium (NO+) and nitroxyl (HNO/NO-) species, has important consequences in NO metabolism. Dinitrosyl iron complex (DNIC) combined with thiol ligands was shown to catalyze the conversion of NO into NO+, resulting in the synthesis of S-nitrosothiols (RSNO) both in vitro and in vivo. The formation mechanism of DNIC was proposed to involve the intermediate release of nitroxyl. Since the detection of hydroxylamine (as the product of a rapid reaction of HNO/NO- with thiols) is taken as the evidence for nitroxyl generation, we examined the formation of hydroxylamine, RSNO, and nitrite (the product of a rapid reaction of NO+ with water) in neutral solutions containing iron ions and thiols exposed to NO under anaerobic conditions. Hydroxylamine was detected in NO treated solutions of iron ions in the presence of cysteine, but not glutathione (GSH). The addition of urate, a major "free" iron-binding agent in humans, to solutions of GSH and iron ions, and the subsequent treatment of these solutions with NO increased the synthesis of GSNO and resulted in the formation of hydroxylamine. This caused a loss of urate and yielded a novel nitrosative/nitration product. GSH attenuated the urate decomposition to such a degree that it could be reflected as the function of GSH:urate. Results described here contribute to the understanding of the role of iron ions in catalyzing the conversion of NO into HNO/NO- and point to the role of uric acid not previously described.
    Nitric Oxide 12/2004; 11(3):256-62. DOI:10.1016/j.niox.2004.09.007 · 3.52 Impact Factor
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    ABSTRACT: Aquaporins (AQPs) are members of the major intrinsic protein (MIP) gene family, a diverse group of water and solute channels found throughout the phyla of plants, animals, and bacteria. Membrane lipid bilayers have an inherently low permeability to water, an attribute that benefits life in aqueous and terrestrial environments. In specialized water-absorbing and secreting cells of mammals, membrane permeability to water is greatly enhanced by the expression of AQPs, a family of membrane proteins which provide channels for osmotically driven water fluxes [1]. An expanding role for mammalian AQPs as pathways for regulated solute transport is becoming evident, and these channels are now proposed to mediate transmembrane fluxes for a growing list of other substrates, including ions, glycerol, and carbon dioxide. Osmotic water and glycerol permeabilities of MIP channels have been described previously in numerous reviews. This review considers a new perspective, focusing on the structural and functional basis of regulated ion channel function in a subset of MIP channels. Even if only a small proportion of water channels function at any given time as ion channels, their contribution may be significant to the physiological function of tissues in which the channels are expressed. Given the fundamental coupling of water and salt fluxes in transport epithelia, and the influence of membrane potential on transport processes, the role of AQPs as regulated ion channels will be of great interest for understanding the physiological and pathophysiological processes of transmembrane transport and signaling in a variety of tissues. Sequence comparisons and electrophysio-logical analyses of these MIP family members reveal structural features that correlate with the properties of activation, block and ionic permeability, particularly for AQP1. Ongoing research promises more intriguing links between structural and functional properties of AQPs.
    Advances in Molecular and Cell Biology 01/2004; 32:351-379. DOI:10.1016/S1569-2558(03)32015-6
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