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Potential roles of nitrate and nitrite in nitric oxide metabolism in the eye.

ABSTRACT: Nitric oxide (NO) signaling has been studied in the eye, including in the pathophysiology of some eye diseases. While NO production by nitric oxide synthase (NOS) enzymes in the eye has been characterized, the more recently described pathways of NO generation by nitrate (NO₃^-) and nitrite (NO₂^-) ions reduction has received much less attention. To elucidate the potential roles of these pathways, we analyzed nitrate and nitrite levels in components of the eye and lacrimal glands, primarily in porcine samples. Nitrate and nitrite levels were higher in cornea than in other eye parts, while lens contained the least amounts. Lacrimal glands exhibited much higher levels of both ions compared to other organs, such as liver and skeletal muscle, and even to salivary glands which are known to concentrate these ions. Western blotting showed expression of sialin, a known nitrate transporter, in the lacrimal glands and other eye components, and also xanthine oxidoreductase, a nitrate and nitrite reductase, in cornea and sclera. Cornea and sclera homogenates possessed a measurable amount of nitrate reduction activity. These results suggest that nitrate ions are concentrated in the lacrimal glands by sialin and can be secreted into eye components via tears and then reduced to nitrite and NO, thereby being an important source of NO in the eye.

SUBMITTER: Park JW

PROVIDER: S-EPMC7406513 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Potential roles of nitrate and nitrite in nitric oxide metabolism in the eye.

Park Ji Won JW Piknova Barbora B Jenkins Audrey A Hellinga David D Parver Leonard M LM Schechter Alan N AN

Scientific reports 20200805 1

Nitric oxide (NO) signaling has been studied in the eye, including in the pathophysiology of some eye diseases. While NO production by nitric oxide synthase (NOS) enzymes in the eye has been characterized, the more recently described pathways of NO generation by nitrate (NO3-) and nitrite (NO2-) ions reduction has received much less attention. To elucidate the potential roles of these pathways, we analyzed nitrate and nitrite levels in components of th ...[more]

PMID: 32759980

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Project description:Nitrate reductases (NRs) are molybdoenzymes that reduce nitrate (NO3 -) to nitrite (NO2 -) in both mammals and plants. In mammals, the salival microbes take part in the generation of the NO2 - from NO3 -, which further produces nitric oxide (NO) either in acid-induced NO2 - reduction or in the presence of nitrite reductases (NiRs). Here, we report a new approach of VCl3 (V3+ ion source) induced step-wise reduction of NO3 - in a CoII-nitrato complex, [(12-TMC)CoII(NO3 -)]+ (2,{CoII-NO3 -}), to a CoIII-nitrosyl complex, [(12-TMC)CoIII(NO)]2+ (4,{CoNO}8), bearing an N-tetramethylated cyclam (TMC) ligand. The VCl3 inspired reduction of NO3 - to NO is believed to occur in two consecutive oxygen atom transfer (OAT) reactions, i.e., OAT-1 = NO3 - → NO2 - (r1) and OAT-2 = NO2 - → NO (r2). In these OAT reactions, VCl3 functions as an O-atom abstracting species, and the reaction of 2 with VCl3 produces a CoIII-nitrosyl ({CoNO}8) with VV-Oxo ({VV[double bond, length as m-dash]O}3+) species, via a proposed CoII-nitrito (3, {CoII-NO2 -}) intermediate species. Further, in a separate experiment, we explored the reaction of isolated complex 3 with VCl3, which showed the generation of 4 with VV-Oxo, validating our proposed reaction sequences of OAT reactions. We ensured and characterized 3 using VCl3 as a limiting reagent, as the second-order rate constant of OAT-2 (k 2 /) is found to be ∼1420 times faster than that of the OAT-1 (k 2) reaction. Binding constant (K b) calculations also support our proposition of NO3 - to NO transformation in two successive OAT reactions, as K b(CoII-NO2 -) is higher than K b(CoII-NO3 -), hence the reaction moves in the forward direction (OAT-1). However, K b(CoII-NO2 -) is comparable to K b{CoNO}8 , and therefore sequenced the second OAT reaction (OAT-2). Mechanistic investigations of these reactions using 15N-labeled-15NO3 - and 15NO2 - revealed that the N-atom in the {CoNO}8 is derived from NO3 - ligand. This work highlights the first-ever report of VCl3 induced step-wise NO3 - reduction (NRs activity) followed by the OAT induced NO2 - reduction and then the generation of Co-nitrosyl species {CoNO}8.

Project description:Background: Exercise and physical activity can improve circulation through various mechanisms, such as the increment of nitric oxide (NO) production, by affecting vascular endothelial nitric oxide synthase, and reducing reactive oxygen species (ROS). Although, theoretically, this mechanism is well known, studies in living subjects have made controversial findings regarding the association of NO production and its metabolites [nitrate/nitrite (NOx)] with physical activity. Hence, this systematic review and meta-analysis was designed to gather all these studies and evaluate the effects of exercise training, and physical activity duration and length on the mean change of serum/plasma NO and NOx. Method: We searched all available bibliographic electronic databases from inception through to May 2022 to include all randomized controlled trials (RCT) and quasi-experimental trials which assessed the effect of exercise and training on NO and NOx levels. Random-effects meta-analysis was used to pool the standardized mean difference (SMD) and 95% confidence interval (CI) of included RCT studies which assessed the effect of training. Stratified meta-analysis was performed according to the type of exercise (high-intensity interval training (HIIT), aerobic training (AT), the duration of exercise (≤8 and > 8 weeks), and length of exercise in each session ≥40 and 40 < minutes). Results: Overall, 15 and 10 studies were included in the systematic review and meta-analysis, respectively. According to the random-effects meta-analysis, exercise significantly increased the mean change of NO and NOx compared to control (SMD: 1.82, 95%CI: 1.14 to 2.49. In the stratified meta-analysis, the mean change of NO and NOx in the intervention group was significantly higher than in the control group in the AT (SMD: 1.36, 95%CI: 0.55-2.18), HIIT (SMD: 2.55, 95%CI: 1.14-3.96), duration of ≤8 (SMD: 2.29, 95%CI: 1.24-3.35) and > 8 weeks (SMD: 1.19, 95%CI: 0.52-1.86), length of ≥40 (SMD: 1.61, 95%CI: 1.04-2.18), and 40 < minutes in each session (SMD: 2.07, 95%CI: 0.79-3.35). Conclusion: The findings of this study indicate that, regardless of exercise duration, length, and type (AT or HIIT), exercise can significantly increase serum NO and NOx levels.

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Potential roles of nitrate and nitrite in nitric oxide metabolism in the eye.

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Potential roles of nitrate and nitrite in nitric oxide metabolism in the eye.

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