Role of inorganic nitrate and nitrite in driving nitric oxide–cGMP‐mediated inhibition of platelet aggregation in vitro and in vivo

Apostoli, GL; Solomon, Antonia; Smallwood, MJ; Winyard, Paul G.; Emerson, Michael

doi:10.1111/jth.12711

Cited by 56 publications

(37 citation statements)

References 58 publications

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“…Given that a background DAF fluorescence was also present in unstimulated platelets in suspension and that some residual DAF fluorescence was observed in platelets adhering to collagen under flow after incubation with L-NMMA, it is possible that NO came in part from the reduction of inorganic nitrite within platelets. 41 We also showed that platelet NO production by individual platelets temporally follows the increase in cytosolic Ca 11 concentration, because in the majority of platelets (.90%), fluorescence for NO was preceded by an intracellular Ca 11 increase, similarly to what was previously shown in smooth muscle cells 42 and endothelial cells. [43][44][45][46] The lag time between the 2 events in platelets (33 6 9.5 s) seems to be longer than that reported in vascular endothelial cells stimulated with bradykinin, in which a delay of ;5 seconds was observed, 45 or in human umbilical cord endothelial cells stimulated with histamine, 46 or in porcine aortic endothelial cells stimulated with thrombin, where almost no lag phase between the 2 events was observed.…”

Section: Blood 22 January 2015 X Volume 125 Number 4 Platelet Nitrisupporting

confidence: 49%

Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Cozzi

Guglielmini

Battiston

et al. 2015

Blood

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• The production of NO by platelets and its possible role are controversial.• We visualize NO formed by single platelets adhering to collagen under flow conditions and show that it depends on Ca 11 and modulates adhesion.Nitric oxide (NO) exerts vasodilatatory, antiplatelet, antioxidant, and antiproliferative effects. Endothelium-derived NO has been shown to be of crucial importance in cardiovascular protection, whereas evidence that NO is synthesized by platelets and regulates platelet function is still controversial. By using a sensitive and specific fluorescent probe, 4-amino-5-methylamino-29,79-difluorofluorescein diacetate (DAF-FM), we visualized NO production in individual platelets undergoing adhesion on a collagen substrate under flow conditions. NO production, monitored in real time, was dependent on the shear rates applied, increasing with the raising of the shear rates. Furthermore, NO production increased in the presence of L-arginine (nitric-oxide synthase [NOS] substrate), and it decreased in the presence of L-NG-monomethyl arginine (L-NMMA) (NOS inhibitor) but not of D-NG-monomethyl arginine (D-NMMA) (L-NMMA-inactive enantiomer). Platelet deposition, measured with mepacrine-labeled platelets, was inversely related to NO production. A correlation was evident between Ca 11 elevation and NO production, suggesting that platelet NO formation is triggered by intracytoplasmic Ca 11 elevation. Simultaneous measurement of NO and Ca 11 indicated that NO production in individual platelets is preceded by Ca 11 elevations, with a lag phase of 33 6 9.5 s. Our studies provide the first direct demonstration of platelet NO production triggered by the interaction with an activating surface under flow and suggest that intraplatelet Ca 11 elevation elicits the production of NO which, in turn, modulates thrombus size. (Blood. 2015;125(4):697-705)

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Section: Blood 22 January 2015 X Volume 125 Number 4 Platelet Nitrisupporting

confidence: 49%

Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Cozzi

Guglielmini

Battiston

et al. 2015

Blood

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“…6 In line with this, inorganic nitrite and nitrate have been shown to inhibit platelet aggregation. 14,17,48,49 On the basis of our current data, showing that esomeprazole interferes with nitrite-or nitrate-mediated effects on blood pressure, it would be interesting to evaluate whether PPIs will also influence the ability of these anions to modulate platelet function. Importantly, in this study, we only looked at one of the parameters known to be affected by nitrate and nitrite, and it remains to be determined whether other effects, including metabolic effects, are also dependent on gastric acidity.…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

et al. 2017

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A n association between chronic use of proton pump inhibitors (PPIs) and increased risk of cardiovascular disease has been implicated. [1][2][3][4][5] For example, it seems that PPIs reduce the efficacy of antiplatelet drugs such as clopidogrel by competing with the hepatic isoenzyme CYP2C19, thereby interfering with its capacity to inhibit platelet aggregation. 6 Other studies have associated chronic use of PPI with increased cardiovascular risk, independently of treatment with clopidogrel 4 or CYP2C19 metabolism. 7,8 In addition, a recent study in diabetic patients indicates that PPIs increase blood pressure. 9 The mechanisms behind these effects are still unclear, but a reduced vascular bioavailability of NO has been suggested. 1 Moreover, it has been speculated that bioactivation of some antiplatelet drugs requires gastric nitrosation under acidic conditions. 10,11 We and others have been studying an alternative NO synthase-independent pathway for NO generation in which inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides in blood and tissues to affect cardiovascular function, including blood pressure.12 Dietary nitrate is absorbed rapidly and is extracted from blood by the salivary glands and greatly concentrated in saliva. In the mouth, commensal bacteria reduce nitrate to the more reactive nitrite anion. Nitrite is then swallowed and enters the acidic stomach where it is nonenzymatically metabolized further to form several potentially bioactive nitrogen oxides, including NO. Orally ingested nitrate clearly has robust NO-like effects systemically, including a decrease in blood pressure, [13][14][15] Abstract-Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg −1), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg −1 min −1 ) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascula...

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“…In platelets, NO is one of the main vascular factors responsible for the inhibition of platelet activation (7,8). Once NO is produced, despite its short half-life, it diffuses in the plasma and smooth muscle and acts as a signaling molecule through activation of soluble guanylate cyclase (sGC) (9). sGC activation catalyzes the formation of the second messenger cGMP and subsequent inhibition of intracellular calcium release, resulting in decreased platelet aggregation.…”

mentioning

confidence: 99%

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Cortí

Xue

Tejero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs. GbX is present in fish erythrocytes and exhibits a nitrite reduction rate up to 200-fold faster than human hemoglobin and up to 50-fold higher than neuroglobin or cytoglobin. Deoxygenated GbX reduces nitrite to form nitric oxide (NO) and potently inhibits platelet activation in vitro, to a greater extent than hemoglobin. Fish RBCs also reduce nitrite to NO and inhibit platelet activation to a greater extent than human RBCs, whereas GbX knockdown inhibits this nitrite-dependent NO signaling. The description of a novel, sixcoordinate globin in RBCs with dominant electron transfer and nitrite reduction functionality provides new insights into the evolved signaling properties of ancestral heme-globins.nitrite | nitric oxide | blood | RBC | platelet

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Role of inorganic nitrate and nitrite in driving nitric oxide–cGMP‐mediated inhibition of platelet aggregation in vitro and in vivo

Cited by 56 publications

References 58 publications

Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Visualization of nitric oxide production by individual platelets during adhesion in flowing blood

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

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