Short-term hypoxic vasodilation<i>in vivo</i>is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction

Umbrello, Michele; Dyson, Alex; Pinto, Bernardo Bollen; Fernandez, Bernadette; Simon, Verena; Feelisch, Martin; Singer, Mervyn

doi:10.1113/jphysiol.2014.255687

Cited by 4 publications

(6 citation statements)

References 36 publications

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“…Recently, Miljkovic et al (106) showed that H 2 S is a rapid mediator of nitrite reduction by providing reducing equivalents to Fe 3 + , thereby generating both NO and its reduced congener, nitroxyl (HNO). Vasodilation produced by acute hypoxia in mice in vivo appears to be independent of NO production, and it is associated with reduced plasma nitrite concentration and increased RSNOs (174). This is consistent with H 2 S, as the initial hypoxic signal that mediates downstream increases in both H 2 S 2 and HNO as shown in Figure 7.…”

Section: Reactions With No and Related Compoundssupporting

confidence: 70%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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Significance: Although oxygen (O 2 )-sensing cells and tissues have been known for decades, the identity of the O 2 -sensing mechanism has remained elusive. Evidence is accumulating that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is this enigmatic O 2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H 2 S synthesis and metabolism have shown that reciprocal H 2 S/O 2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O 2 controls H 2 S inactivation, and the effects of H 2 S on downstream signaling events are consistent with those activated by hypoxia. H 2 S-mediated O 2 sensing has been demonstrated in a variety of O 2 -sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H 2 S and its metabolites. Future Directions: Development of specific inhibitors of H 2 S metabolism and effector activation as well as cellular organelle-targeted compounds that release H 2 S in a timeor environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397.

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Section: Reactions With No and Related Compoundssupporting

confidence: 70%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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“…The formation of NO from nitrite was found to be largely enzymatic in nature as it was sensitive to heat inactivation and blockage of thiol groups , supporting earlier studies implicating heme and thiolcontaining reductases in this process (Bryan et al, 2005). Data from a more recent in vivo study carried out in rats suggest that acute hypoxic vasodilatation is largely mediated by NO metabolites rather than by free NO from Hb-mediated nitrite reduction (Umbrello et al, 2014).…”

Section: Role Of Nitrite At Different Oxygen Tensionssupporting

confidence: 68%

“…Both Hb (Basu et al, 2007) and carbonic anhydrase (Aamand et al, 2009) have been reported to possess nitrite/nitrous acid anhydrase activity, a reaction in the course of which N 2 O 3 is formed, eventually giving rise to NO and NO 2 . While the former could theoretically provide a convenient way of exporting nitrite-derived NO from RBCs under hypoxic conditions, recent animal experimental results suggest that the majority of hypoxic vasodilatation is not mediated by Hbmediated nitrite reduction (Umbrello et al, 2014). The nitrite reductase activity of carbonic anhydrase appears to be linked to the coupling of cerebral blood flow and metabolic activity in response to visual stimulation (Aamand et al, 1985(Aamand et al, , 2009.…”

Section: Mechanisms Of Nitrite-mediated Vasodilatationmentioning

confidence: 99%

“…In addition, there is increasing evidence that nitrite reduction may occur via blood borne protein mediated mechanisms such as RBC eNOS, as demonstrated by Webb et al (2008a) and Wood et al (2013), as opposed to or in addition to the currently favoured vascular tissue-derived NO. Also of interest is recent work by Umbrello et al (2014) who have demonstrated that short-term hypoxic vasodilatation may be mediated by bioactive NO metabolites rather than by free NO. These recent findings are of great interest in terms of the perceived "physiology" of nitrite but require further substantiation and independent confirmation by other groups.…”

Section: Mechanisms Of Nitrite-mediated Vasodilatationmentioning

confidence: 99%

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Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

Bailey

Feelisch

Horowitz

et al. 2014

Pharmacology & Therapeutics

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Nitrite has emerged as an important bioactive molecule that can be biotransformed to nitric oxide (NO) related metabolites in normoxia and reduced to NO under hypoxic and acidic conditions to exert vasodilatory effects and confer a variety of other benefits to the cardiovascular system. Abundant research is currently underway to understand the mechanisms involved and define the role of nitrite in health and disease. In this review we discuss the impact of nitrite and dietary nitrate on vascular function and the potential therapeutic role of nitrite in acute heart failure.

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“…It is well established that several of the enzymes that reduce nitrite to NO operate more efficiently during hypoxia. Umbrello and colleagues demonstrated that vasodilatation by nitrite in vivo was more potent during hypoxia and this was also conferred through bioactive metabolites rather than free NO [25]. We evaluated the effects of low oxygenation and low pH separately.…”

Section: Discussionmentioning

confidence: 96%