Evaluation of pediatric patients for intestinal transplantation in the modern era.

OBJECTIVES: To review recent evaluations of pediatric patients with intestinal failure (IF) for intestinal transplantation (ITx), waiting list decisions, and outcomes of patients listed and not listed for ITx at our center. METHODS: Retrospective chart review of 97 patients evaluated for ITx from January 2014 to December 2021 including data from referring institutions and protocol laboratory testing, body imaging, endoscopy, and liver biopsy in selected cases. Survival analysis used Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Patients were referred almost entirely from outside institutions, one-third because of intestinal failure-associated liver disease (IFALD), two-thirds because of repeated infective and non-IFALD complications under minimally successful intestinal rehabilitation, and a single patient because of lost central vein access. The majority had short bowel syndrome (SBS). Waiting list placement was offered to 67 (69%) patients, 40 of whom for IFALD. The IFALD group was generally younger and more likely to have SBS, have received more parenteral nutrition, have demonstrated more evidence of chronic inflammation and have inferior kidney function compared to those offered ITx for non-IFALD complications and those not listed. ITx was performed in 53 patients. Superior postevaluation survival was independently associated with higher serum creatinine (hazard ratio [HR] 15.410, p = 014), whereas inferior postevaluation survival was associated with ITx (HR 0.515, p = 0.035) and higher serum fibrinogen (HR 0.994, p = 0.005). CONCLUSIONS: Despite recent improvements in IF management, IFALD remains a prominent reason for ITx referral. Complications of IF inherent to ITx candidacy influence postevaluation and post-ITx survival.

The Efficacy of Nitric Oxide-Generating Lozenges on Outcome in Newly Diagnosed COVID-19 Patients of African American and Hispanic Origin.

BACKGROUND: The study was initiated in 2020 to test the efficacy of a nitric oxide-generating lozenge (NOL) in outpatients with newly diagnosed COVID-19 to mitigate disease severity. The study enrolled high-risk patients, African American and Latino. METHODS: This was a randomized, double-blinded, prospective, placebo-controlled trial. The primary endpoint was hospitalization, intensive care unit admission, intubation, dialysis, and death. The secondary endpoints were time to symptom resolution and the effect on oxygen saturation. Patients ages 50-85 years with recent COVID-19 diagnosis with at least one risk factor were recruited. Patients were randomized to either active treatment or placebo using block randomization. Blood pressure and oxygen saturation (SpO2) was measured prior to and after the first dose and each morning thereafter. RESULTS: A total of 840 patients was planned, half in each of the lozenge and placebo groups. An interim review of data was prespecified. Of 524 patients, the composite endpoint occurred in 6 patients, 3 (1.1%) in each group. The time to symptom resolution was 1 day shorter on active treatment (8.7 ± 6.6 vs 9.8 ± 6.8 days) (P = .3). There was no change in SpO2 on placebo (0.0 ± 2.0%) and no significant change on treatment (0.14 ± 0.9%), P = .3. All events occurred in the first year (2020). CONCLUSIONS: This study did not find a benefit of NOL therapy in COVID-19 patients and was terminated for futility. NOL treatment did not reduce mortality, hospitalization, intubation, or a reduction in symptoms duration. The study did find the NO lozenges were well tolerated in high-risk patients, without reported side effects.

Dietary nitrate biochemistry and physiology. An update on clinical benefits and mechanisms of action.

It is now more than 35 years since endothelium derived relaxing factor was identified as nitric oxide (NO). The last few decades have seen an explosion around nitric oxide biochemistry, physiology and clinical translation. The science reveals that all chronic disease is associated with decreased blood flow to the affected organ which results in increased inflammation, oxidative stress and immune dysfunction. This is true for cardiovascular disease, neurological disease, kidney, lung, liver disorders and every other major disorder. Since nitric oxide controls and regulates blood flow, oxygen and nutrient delivery to every cell, tissue and organ in the body and also mitigates inflammation, oxidative stress and immune dysfunction, a focus on restoring nitric oxide production is an obvious therapeutic strategy for a number of poorly managed chronic diseases. Since dietary nitrate is a major contributor to endogenous nitric oxide production, it should be considered as a means of therapy and restoration of nitric oxide. This review will update on the current state of the science and effects of inorganic nitrate administered through the diet on several chronic conditions and reveal how much is needed. It is clear now that antiseptic mouthwash and use of antacids disrupt nitrate metabolism to nitric oxide leading to clinical symptoms of nitric oxide deficiency. Based on the science, nitrate should be considered an indispensable nutrient that should be accounted for in dietary guidelines.

Nitric oxide deficiency is a primary driver of hypertension.

Hypertension remains a global health crisis. High blood pressure is the number one modifiable risk factor in the onset and progression of cardiovascular disease. Despite many different classes of drug therapies approved for hypertension, the use of polypharmacy and recommendations on lifestyle modification, many patients still suffer from uncontrolled or unmanaged hypertension. Nitric oxide is a naturally produced vasodilator that controls and regulates vascular tone and therefore controls and regulates blood pressure. Research over the past 40 years reveals that loss of nitric oxide production, termed endothelial dysfunction, is the earliest event in the development of hypertension. Strategies aimed at preventing the loss of nitric oxide production and/or therapeutic strategies designed to restore nitric oxide production will likely have a positive effect on patients' health and lead to better management of blood pressure. This review article will focus on the loss of nitric oxide production as the primary contributor to hypertension and also discuss safe and clinically proven strategies to restore nitric oxide production and recapitulate nitric oxide based signaling in humans.

The oral microbiome, nitric oxide and exercise performance.

The human microbiome comprises ∼1013-1014 microbial cells which form a symbiotic relationship with the host and play a critical role in the regulation of human metabolism. In the oral cavity, several species of bacteria are capable of reducing nitrate to nitrite; a key precursor of the signaling molecule nitric oxide. Nitric oxide has myriad physiological functions, which include the maintenance of cardiovascular homeostasis and the regulation of acute and chronic responses to exercise. This article provides a brief narrative review of the research that has explored how diversity and plasticity of the oral microbiome influences nitric oxide bioavailability and related physiological outcomes. There is unequivocal evidence that dysbiosis (e.g. through disease) or disruption (e.g. by use of antiseptic mouthwash or antibiotics) of the oral microbiota will suppress nitric oxide production via the nitrate-nitrite-nitric oxide pathway and negatively impact blood pressure. Conversely, there is preliminary evidence to suggest that proliferation of nitrate-reducing bacteria via the diet or targeted probiotics can augment nitric oxide production and improve markers of oral health. Despite this, it is yet to be established whether purposefully altering the oral microbiome can have a meaningful impact on exercise performance. Future research should determine whether alterations to the composition and metabolic activity of bacteria in the mouth influence the acute responses to exercise and the physiological adaptations to exercise training.

The effect of continuous venovenous hemodiafiltration on amino acid delivery, clearance, and removal in children.

BACKGROUND: In critically ill children with acute kidney injury (AKI), continuous kidney replacement therapy (CKRT) enables nutrition provision. The magnitude of amino acid loss during continuous venovenous hemodiafiltration (CVVHDF) is unknown and needs accurate quantification. We investigated the mass removal and clearance of amino acids in pediatric CVVHDF. METHODS: This is a prospective observational cohort study of patients receiving CVVHDF from August 2014 to January 2016 in the pediatric intensive care unit (PICU) of a tertiary children's hospital. RESULTS: Fifteen patients (40% male, median age 2.0 (IQR 0.7, 8.0) years) were enrolled. Median PICU and hospital lengths of stay were 20 (9, 59) and 36 (22, 132) days, respectively. Overall survival to discharge was 66.7%. Median daily protein prescription was 2.00 (1.25, 2.80) g/kg/day. Median daily amino acid mass removal was 299.0 (174.9, 452.0) mg/kg body weight, and median daily amino acid mass clearance was 18.2 (13.5, 27.9) ml/min/m2, resulting in a median 14.6 (8.3, 26.7) % protein loss. The rate of amino acid loss increased with increasing dialysis dose and blood flow rate. CONCLUSION: CVVHDF prescription and related amino acid loss impact nutrition provision, with 14.6% of the prescribed protein removed. Current recommendations for protein provision for children requiring CVVHDF should be adjusted to compensate for circuit-related loss. A higher resolution version of the Graphical abstract is available as Supplementary information.

Polyester Mesh Functionalization with Nitric Oxide-Releasing Silica Nanoparticles Reduces Early Methicillin-Resistant Staphylococcus aureus Contamination.

Background: Infected hernia mesh is a cause of post-operative morbidity. Nitric oxide (NO) plays a key role in the endogenous immune response to infection. We sought to study the efficacy of a NO-releasing mesh against methicillin-resistant Staphylococcus aureus (MRSA). We hypothesized that a NO-releasing polyester mesh would decrease MRSA colonization and proliferation. Materials and Methods: A composite polyester mesh functionalized with N-diazeniumdiolate silica nanoparticles was synthesized and characterized. N-diazeniumdiolate silica parietex composite (NOSi) was inoculated with 104,106, or 108 colony forming units (CFUs) of MRSA and a dose response was quantified in a soy tryptic broth assay. Utilizing a rat model of contaminated hernia repair, implanted mesh was inoculated with MRSA, recovered, and CFUs were quantified. Clinical metrics of erythema, mesh contracture, and adhesion severity were then characterized. Results: Methicillin-resistant Staphylococcus aureus CFUs demonstrated a dose-dependent response to NOSi in vitro. In vivo, quantified CFUs showed a dose-dependent response to NOSi-PCO. Treated rats had fewer severe adhesions, less erythema, and reduced mesh contracture. Conclusions: We demonstrate the efficacy of a NO-releasing mesh to treat MRSA in vitro and in vivo. Creation of a novel class of antimicrobial prosthetics offers new strategies for reconstructing contaminated abdominal wall defects and other procedures that benefit from deploying synthetic prostheses in contaminated environments.

Inorganic Nitrite Supplementation Improves Endothelial Function With Aging: Translational Evidence for Suppression of Mitochondria-Derived Oxidative Stress.

[Figure: see text].

A systemic review on the antioxidant and anti-inflammatory effects of resveratrol, curcumin, and dietary nitric oxide supplementation on human cardiovascular health.

The potential benefits of supplemental nutrients and dietary interventions against cardiovascular morbidity and mortality have been extensively investigated throughout the years. Numerous supplements claim cardioprotection and reduction of cardiovascular risk factors, but the roles of many supplements have not been determined. In the vast number of supplements on the market asserting cardioprotective effects, only 3 have been thoroughly evaluated and consistently reported as effective by our clinic patients. They have used supplements such as fish oil, multivitamins, and calcium, but many had not known of the benefits of resveratrol, curcumin, and nitric oxide as supplements for improving cardiovascular health. The cardioprotective effects of these dietary supplements in both animal models and humans have been explored with proposed mechanisms of action mostly attributed to antioxidant and anti-inflammatory properties. Resveratrol is one of the most studied polyphenols with established cardiovascular benefits. Preclinical studies have demonstrated these effects exerted via improved inflammatory markers, atherogenic profile, glucose metabolism, and endothelial function and are further supported by clinical trials. Curcumin has a well-established anti-inflammatory role by regulating numerous transcription factors and cytokines linked to inflammation. Inflammation is an underlying pathology in cardiovascular diseases, rendering curcumin a potential therapeutic compound. Similarly, nitric oxide supplementation has demonstrated cardiovascular benefits by normalizing blood pressure; enhancing blood flow; and reducing inflammation, immune dysfunction, and oxidative stress. A comprehensive review was performed evaluating the cardioprotective effects of these 3 dietary supplements with hope to provide updated information, promote further awareness of these supplements, and inspire future studies on their effects on cardiovascular health.

Association of Plasma Levels of Nitric Oxide Oxidative Metabolites with Acute Stroke in Patients Presenting to the Emergency Department of a Low-Middle Income Country.

INTRODUCTION: Acute stroke incites an inflammatory reaction in the brain's microvasculature, activating formation of nitric oxide oxidative metabolites, nitrate and nitrite (NOx, collectively), measurable in plasma. Our objectives were to investigate plasma NOx in patients with acute stroke presenting to the Emergency Department (ED) and to determine if it could (i) differentiate between ischemic and hemorrhagic stroke; (ii) predict clinical outcomes. METHODS: A cross-sectional study was conducted in the ED of Aga Khan University Hospital, from January 1 to December 31, 2016. Participants were enrolled if they had clinical acute stroke with confirmatory brain imaging to differentiate between ischemia and hemorrhage. Clinical demographic information, ancillary blood, and diagnostic specimens were collected as per standard of care since the center follows stroke algorithmic guidelines. Plasma NOx analysis was performed using high performance liquid chromatography. Clinical outcomes were assessed using Barthel Index and Modified Rankin Score. Data was analyzed using SPSS 19 and expressed in medians with interquartile ranges. Nonparametric tests were applied for comparing among groups. Pearson's correlation was used to determine associations with aforementioned stroke severity and disability scales. RESULTS: Seventy-five patients were enrolled, with median age of 57 years (IQR 47-66 years), 53 (71%) were males, and 46 (61%) had ischemic stroke. Overall, median NOx was 20.8 µM (IQR 13.4-35.3); there was no statistically significant difference between NOx in ischemic versus hemorrhagic stroke (21.2 µM vs. 17.9 µM; p=0.2). However, there was a significant positive correlation between NOx levels and aforementioned acute stroke scales [r(73)=0.417, p=0.0001], for both. CONCLUSION: Although plasma NOx could not differentiate between ischemia and hemorrhage, higher levels of the biomarker did show associations with poststroke disability scales. Further study with more patients in a multicenter trial is warranted to establish the real biomarker potential of plasma NOx in acute stroke.

Update on Gaseous Signaling Molecules Nitric Oxide and Hydrogen Sulfide: Strategies to Capture their Functional Activity for Human Therapeutics.

Discovery of the production of gaseous molecules, such as nitric oxide and hydrogen sulfide, within the human body began a new concept in cellular signaling. Over the past 30 years, these molecules have been investigated and found to have extremely important beneficial effects in numerous chronic diseases. Gaseous signaling molecules that diffuse in three dimensions apparently contradict the selectivity and specificity afforded by normal ligand receptor binding and activation. This new concept has also created hurdles in the development of safe and efficacious drug therapy based on these molecules. Mechanisms involving formation of more stable intermediates and second messengers allow for new strategies for safe and effective delivery of these molecules for human disease. The purpose of this review is to highlight the biologic effects of nitric oxide and hydrogen sulfide, their seemingly indistinguishable effects, and how these molecules can be safely harnessed for drug development and precursors or substrates administered for human consumption through applied physiology.

Frequency of Tongue Cleaning Impacts the Human Tongue Microbiome Composition and Enterosalivary Circulation of Nitrate.

The oral microbiome has the potential to provide an important symbiotic function in human blood pressure physiology by contributing to the generation of nitric oxide (NO), an essential cardiovascular signaling molecule. NO is produced by the human body via conversion of arginine to NO by endogenous nitric oxide synthase (eNOS) but eNOS activity varies by subject. Oral microbial communities are proposed to supplement host NO production by reducing dietary nitrate to nitrite via bacterial nitrate reductases. Unreduced dietary nitrate is delivered to the oral cavity in saliva, a physiological process termed the enterosalivary circulation of nitrate. Previous studies demonstrated that disruption of enterosalivary circulation via use of oral antiseptics resulted in increases in systolic blood pressure. These previous studies did not include detailed information on the oral health of enrolled subjects. Using 16S rRNA gene sequencing and analysis, we determined whether introduction of chlorhexidine antiseptic mouthwash for 1 week was associated with changes in tongue bacterial communities and resting systolic blood pressure in healthy normotensive individuals with documented oral hygiene behaviors and free of oral disease. Tongue cleaning frequency was a predictor of chlorhexidine-induced changes in systolic blood pressure and tongue microbiome composition. Twice-daily chlorhexidine usage was associated with a significant increase in systolic blood pressure after 1 week of use and recovery from use resulted in an enrichment in nitrate-reducing bacteria on the tongue. Individuals with relatively high levels of bacterial nitrite reductases had lower resting systolic blood pressure. These results further support the concept of a symbiotic oral microbiome contributing to human health via the enterosalivary nitrate-nitrite-NO pathway. These data suggest that management of the tongue microbiome by regular cleaning together with adequate dietary intake of nitrate provide an opportunity for the improvement of resting systolic blood pressure.

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension.

Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.

Functional Nitric Oxide Nutrition to Combat Cardiovascular Disease.

PURPOSE OF REVIEW: To reveal the mechanisms of nitric oxide (NO) production in humans and how lifestyle, drug therapy, and hygienic practices can decrease NO production. Furthermore, to show how functional nitric oxide nutrition can overcome these limitations to restore endogenous NO production and combat cardiovascular disease. RECENT FINDINGS: Research over the past decade has revealed that inorganic nitrate and nitrite found naturally in green leafy vegetables and other vegetables such as beets can provide the human body with a source of bioactive nitric oxide. NO is one of the most important molecules produced within the cardiovascular system that maintains normal blood pressure and prevents inflammation, immune dysfunction, and oxidative stress, hallmarks of cardiovascular disease. This pathway is dependent upon the amount of inorganic nitrate and nitrite in the foods we eat, the presence of oral nitrate-reducing bacteria, and sufficient stomach acid production. The concept of food being medicine and medicine being food has lost its place in the practice and implementation of modern medicine over the past century. Certain dietary patterns and specific foods are known to confer very significant protective effects for many human diseases, including cardiovascular disease, the number one killer of men and women in the developed world. However, identification of single or multiple bioactive molecules that are responsible for these effects has escaped scientists and nutritionists for many years. This review will highlight the biochemical, physiological, and epidemiological basis for functional nitric oxide nutrition that can be safely and effectively utilized in patients.

Inorganic nitrate supplementation attenuates peripheral chemoreflex sensitivity but does not improve cardiovagal baroreflex sensitivity in older adults.

Aging is associated with increased peripheral chemoreceptor activity, reduced nitric oxide (NO) bioavailability, and attenuation of cardiovagal baroreflex sensitivity (BRS), collectively increasing the risk of cardiovascular disease. Evidence suggests that NO may attenuate peripheral chemoreflex sensitivity and increase BRS. Exogenous inorganic nitrate ([Formula: see text]) increases NO bioavailability via the [Formula: see text]-[Formula: see text]-NO pathway. Our hypothesis was that inorganic [Formula: see text] supplementation would attenuate peripheral chemoreflex sensitivity and enhance spontaneous cardiovagal BRS in older adults. We used a randomized, placebo-controlled crossover design in which 13 older (67 ± 3 yr old) adults ingested beetroot powder containing (BRA) or devoid of (BRP) [Formula: see text] and [Formula: see text] daily over 4 wk. Spontaneous cardiovagal BRS was assessed over 15 min of rest and was quantified using the sequence method. Chemoreflex sensitivity was assessed via ~5 min of hypoxia (10% fraction of inspired O2) and reported as the slope of the relationship between O2 saturation (%[Formula: see text]) and minute ventilation (in l/min) or heart rate (in beats/min). Ventilatory responsiveness to hypoxia was reduced after BRA (from -0.14 ± 0.04 to -0.05 ± 0.02 l·min-1·%[Formula: see text]-1, P = 0.01) versus BRP (from -0.10 ± 0.05 to -0.11 ± 0.05 l·min-1·%[Formula: see text]-1, P = 0.80), with no differences in heart rate responsiveness (BRA: from -0.47 ± 0.06 to -0.33 ± 0.04 beats·min-1·%[Formula: see text]-1, BRP: from -0.48 ± 0.07 to -0.42 ± 0.06 beats·min-1·%[Formula: see text]-1) between conditions (interaction effect, P = 0.41). Spontaneous cardiovagal BRS was unchanged after BRA and BRP (interaction effects, P = 0.69, 0.94, and 0.39 for all, up, and down sequences, respectively), despite a reduction in resting systolic and mean arterial blood pressure in the experimental (BRA) group ( P < 0.01 for both). These findings illustrate that inorganic [Formula: see text] supplementation attenuates peripheral chemoreflex sensitivity without concomitant change in spontaneous cardiovagal BRS in older adults. NEW & NOTEWORTHY Exogenous inorganic nitrate supplementation attenuates ventilatory, but not heart rate, responsiveness to abbreviated hypoxic exposure in older adults. Additionally, inorganic nitrate reduces systolic and mean arterial blood pressure without affecting spontaneous cardiovagal baroreflex sensitivity. These findings suggest that inorganic nitrate may attenuate sympathetically oriented pathologies associated with aging.

Biomarkers in Pulmonary Vascular Disease: Gauging Response to Therapy.

Biomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy.

Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure.

Having high blood pressure puts you at risk for heart disease and stroke, which are leading causes of death in the USA and worldwide. One out of every three Americans has hypertension, and it is estimated that despite aggressive treatment with medications, only about half of those medicated have managed blood pressure. Recent discoveries of the oral microbiome that reduces inorganic nitrate to nitrite and nitric oxide provide a new therapeutic target for the management of hypertension. The presence or absence of select and specific bacteria may determine steady-state blood pressure levels. Eradication of oral bacteria through antiseptic mouthwash or overuse of antibiotics causes blood pressure to increase. Allowing recolonization of nitrate- and nitrite-reducing bacteria can normalize blood pressure. This review will provide evidence of the link between oral microbiota and the production of nitric oxide and regulation of systemic blood pressure. Management of systemic hypertension through maintenance of the oral microbiome is a completely new paradigm in cardiovascular medicine.

Nebivolol Acts as a S-Nitrosoglutathione Reductase Inhibitor: A New Mechanism of Action.

BACKGROUND AND PURPOSE: Published data on nebivolol reveal selective ß1 adrenergic selectively along with novel nitric oxide (NO)-dependent vasodilatory properties. However, the exact molecular mechanism is unknown. Protein S-nitrosylation constitutes a large part of the ubiquitous influence of NO on cellular signal transduction and is involved in a number of human diseases. More recently, protein denitrosylation has been shown to play a major role in controlling cellular S-nitrosylation (SNO). Several enzymes have been reported to catalyze the reduction of SNOs and are viewed as candidate denitrosylases. One of the first described is known as S-nitrosoglutathione reductase (GSNOR). Importantly, GSNOR has been shown to play a role in regulating SNO signaling downstream of the ß-adrenergic receptor and is therefore operative in cellular signal transduction. Pharmacological inhibition or genetic deletion of GSNOR leads to enhanced vasodilation and characteristic of known effects of nebivolol. Structurally, nebivolol is similar to known inhibitors of GSNOR. Therefore, we hypothesize that some of the known effects of nebivolol may occur through this mechanism. EXPERIMENTAL APPROACH: Using cell culture systems, tissue organ bath, and intact animal models, we report that nebivolol treatment leads to a dose-dependent accumulation of nitrosothiols in cells, and this is associated with an enhanced vasodilation by S-nitrosoglutathione. KEY RESULTS: These data suggest a new mechanism of action of nebivolol that may explain in part the reported NO activity. CONCLUSIONS AND IMPLICATIONS: Because exogenous mediators of protein SNO or denitrosylation can substantially affect the development or progression of disease, this may call for new utility of nebivolol.

Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults.

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically (P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased ß-stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial.