Evaluation and comparison of the effects of a new paste containing 8% L-Arginine and CaCO3 plus KNO3 on dentinal tubules occlusion and dental sensitivity: a randomized, triple blinded clinical trial study.

BACKGROUND: Dentin hypersensitivity, often occurring after dental treatments or from erosive lesions, is a prevalent patient complaint. This study introduces a paste combining 8% L-arginine, calcium carbonate, and potassium nitrate to evaluate its impact on dentinal tubules occlusion, dentin permeability, and tooth sensitivity. METHODS: Dentin surfaces from 24 third molars (thickness: 2 mm) were divided into two groups of 12. One received the experimental paste, while the other received a placebo without desensitizer. Permeability and sealing ability were assessed through scanning electron microscopy (SEM) and dentin permeability measurement. The pastes' effects on hypersensitivity were then examined in a triple-blind, randomized parallel-armed clinical trial with 16 eligible patients. Sensitivity to cold, touch, and spontaneous stimuli was recorded using the VAS scale at various intervals post-treatment. Statistical analysis was conducted using Shapiro-Wilk, Mann-Whitney U, Friedman, and Wilcoxon tests (α = 0.05). RESULTS: The permeability test demonstrated a significant reduction in dentin permeability in the experimental group (P = 0.002) compared to the control (P = 0.178). SEM images revealed most dentinal tubules in the intervention samples to be occluded. Clinically, both groups showed a significant decrease in the three types of evaluated sensitivity throughout the study. However, no significant difference in sensitivities between the two groups was observed, with the exception of cold sensitivity at three months post-treatment (P = 0.054). CONCLUSION: The innovative desensitizing paste featuring 8% L-arginine, calcium carbonate, and potassium nitrate effectively occluded dentinal tubules and reduced dentin permeability. It mitigated immediate and prolonged dentin hypersensitivity to various stimuli, supporting its potential role in managing dentin hypersensitivity. TRIAL REGISTRATION: http://irct.ir : IRCT20220829055822N1, September 9th, 2022.

Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial.

BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported. METHODS: NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov: NCT03627130. RESULTS: Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P < .001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13-0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P = .003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94-7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P = .001) vs. placebo. CONCLUSIONS: In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo.

Anal fissures: An update on treatment options.

BACKGROUND: Anal fissure (AF) is the second most common anorectal complaint in healthcare settings. The presentation might be acute or chronic, characterised by severe pain with defaecation that persists for one to two hours. Non-surgical and surgical interventions are available based on the severity and persistence of the fissure. OBJECTIVE: The aim of this article is to review the pathophysiology, clinical presentation and management of AF under current guidelines. DISCUSSION: The aetiology of AF is unclear, although it is commonly associated with local trauma or associated chronic conditions. Acute AF is first treated with conservative therapy, including dietary fibre and sitz baths. Addition of topical nitrates, topical calcium channel blockers or botulinum toxin injection is indicated with failure of conservative treatment or at medical discretion. Surgical options are considered if AF persists despite treatment. Most present as hypertonic, but special consideration is needed for hypotonic or secondary presentations.

Risk of Death in Patients With Coronary Artery Disease Taking Nitrates and Phosphodiesterase-5 Inhibitors.

BACKGROUND: Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication. OBJECTIVES: The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication. METHODS: Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE). RESULTS: In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83). CONCLUSIONS: The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted.

Which patients with coronary artery disease should include oral nitrates on their discharge medication list?

BACKGROUND: Which patients with coronary artery disease (CAD) should have oral nitrates on their discharge medication list after coronary angiography (CAG)? To assess the relationship between oral nitrates included in the discharge medication list and major adverse cardiovascular events (MACEs) among CAD patients, we designed this retrospective cohort study. METHODS: A total of 2979 CAD patients hospitalised in the Department of Cardiology, Affiliated Hospital of Jining Medical University from May 2013 to October 2015 were enrolled, grouped according to whether oral nitrates were included at discharge after CAG, and followed up for MACEs for a mean of 4.42 years after discharge. The primary endpoint was MACEs. Multivariate Cox proportional hazards models were used to analyses potential confounding factors. Stratified analysis was used to observe the relationship between oral nitrates and MACEs by different covariates. RESULTS: The median follow-up time was 4.61 years, and 296 (9.94%) patients experienced MACEs. Multivariate Cox proportional hazards model analysis showed no association between oral nitrates on the discharge medication list and the occurrence of MACEs among patients with CAD (p > 0.05) after adjusting for some covariates, such as SYNTAX score (hazard ratio (HR): 1.18, 95% confidence interval (CI): 0.90-1.55, p = 0.2420). Stratified analysis revealed a higher incidence of MACEs among hypertensive patients prescribed oral nitrates at discharge (HR: 1.67, 95% confidence CI: 1.13-2.46, p = 0.0046). However, prescribing nitrates at discharge for patients with low uric acid levels increased the incidence of MACEs, which showed a possible trend towards significance (HR: 1.44, 95% CI: 0.99-2.09, p = 0.0525). CONCLUSION: There was no association between oral nitrates included in the discharge medication list and the development of MACEs among patients with CAD after adjusting for some covariates, such as SYNTAX score. Oral nitrates after discharge for CAD patients combined with hypertension increased the occurrence of MACEs. Oral nitrates after discharge for CAD patients combined with low uric acid levels may increase theoccurrence of MACEs, and close monitoring for any adverse events is recommended.

A review on nitrates' health benefits and disease prevention.

Dietary nitrates (NO3-) are naturally occurring compounds in various vegetables, especially beetroot, which is mainly supplemented in the form of BRJ. Dietary nitrates (NO3-) play a crucial function in human physiology. On consumption, nitrates (NO3-) undergo a conversion process, producing nitric oxide (NO) via a complex metabolic pathway. Nitric oxide (NO) is associated with many physiological processes, entailing immune modulation, neurotransmission, and vasodilation, enabling blood vessel dilation and relaxation, which boosts blood flow and oxygen delivery to tissues, positively influencing cardiovascular health, exercise performance, and cognitive function. There are various analytical processes to determine the level of nitrate (NO3-) present in dietary sources. The impact of dietary nitrates (NO3-) can differ among individuals. Thus, the review revisits the dietary source of nitrates (NO3-), its metabolism, absorption, excretion, analytical techniques to assess nitrates (NO3-) content in various dietary sources, and discusses health effects.

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.

BACKGROUND: Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.

Dietary nitrate supplementation to enhance exercise capacity in patients with COPD: Evidence from a meta-analysis of randomized controlled trials and a network pharmacological analysis.

OBJECTIVE: The potential effects of nitrate in patients with chronic obstructive pulmonary disease (COPD) have attracted increased research interest. However, previous clinical trials have reported inconsistent results, and consecutive meta-analyses have failed to reach a consensus. Since some randomized controlled trials have recently been conducted that can provide more evidence, we performed an updated meta-analysis. METHODS: A comprehensive literature search was conducted using PubMed, the Cochrane Library, Embase, and Web of Science databases to identify trials that assessed the efficacy and safety of nitrate in patients with COPD. The Revman 5.3 software was used for data analysis. Mean difference (MD) or standardized mean difference (SMD) with 95 % confidence interval (CI) was used as the effect measure, and forest plots were used to display individual and pooled results. Network pharmacology analysis was conducted to investigate the potential mechanisms of nitrate action in COPD. RESULTS: Eleven studies involving 287 patients were included in this meta-analysis. The results indicated that dietary nitrate supplementation increased plasma nitrate and nitrite concentrations and fractional exhaled nitric oxide in patients with COPD. Nitrate improved exercise capacity [SMD = 0.38, 95 % CI = 0.04-0.72] and endothelial function [MD = 9.41, 95 % CI = 5.30-13.52], and relieved dyspnea in patients with COPD. Network pharmacology identified AKT1, IL1B, MAPK3, and CASP3 as key treatment targets. CONCLUSION: Dietary nitrate supplementation could be used as a potential treatment for patients with COPD, especially to increase their exercise capacity. The underlying mechanisms may be related to AKT1, IL1B, MAPK3, and CASP3.

l-Arginine/nitric oxide pathway and oxidative stress in adults with ADHD: Effects of methylphenidate treatment.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication. METHODS: In plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry. RESULTS: Of the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 µM [46.2-76.0] vs. CO 44.4 µM [35.0-52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 µM [2.26-3.27]) vs. CO (2.13 µM [1.50-2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 µM [128-159]; +MPH 96.2 µM [70.2-140]; Co 75.9 µM [62.0-94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups. CONCLUSION: Adult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress.

Efficacy of beetroot juice on reducing blood pressure in hypertensive adults with autosomal dominant polycystic kidney disease (BEET-PKD): study protocol for a double-blind, randomised, placebo-controlled trial.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD) impaired nitric oxide (NO) synthesis, in part, contributes to early-onset hypertension. Beetroot juice (BRJ) reduces blood pressure (BP) by increasing NO-mediated vasodilation. The aim of this double-blind, randomised, placebo-controlled study is to test the hypothesis that BRJ reduces systolic and diastolic clinic BP in hypertensive adults with ADPKD. METHODS: Participants with ADPKD and treated hypertension (n = 60) will be randomly allocated (1:1) to receive a daily dose of either nitrate-replete (400 mg nitrate/day) or nitrate-deplete BRJ for 4 weeks. The co-primary outcomes are change in mean systolic and diastolic clinic BP before and after 4 weeks of treatment with daily BRJ. Secondary outcomes are changes in daily home BP, urinary albumin to creatinine ratio, serum and salivary nitrate/nitrite levels and serum asymmetric dimethylarginine levels before and after 4 weeks of BRJ. DISCUSSION: The effect of BRJ in ADPKD has not been previously tested. BRJ is an accessible, natural dietary supplement that, if effective, will provide a novel adjunctive approach for treating hypertension in ADPKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05401409. Retrospectively registered on 27th May 2022.

Determining effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of clinical strains of Pseudomonas aeruginosa in biofilm-inspired alginate encapsulates.

BACKGROUND: Biofilms play a role in recalcitrance and treatability of bacterial infections, but majority of known antibiotic resistance mechanisms are biofilm-independent. Biofilms of Pseudomonas aeruginosa, especially in cystic fibrosis patients infected with the alginate producing strains in their lungs, are hard to treat. Changes in growth-related bacterial metabolism in biofilm affect their antibiotic recalcitrance which could be considered for new therapies designed based on these changes. In this study, effects of nitrate, arginine, and ferrous were investigated on antibiotic recalcitrance in alginate-encapsulated P. aeruginosa strains isolated from cystic fibrosis patients in the presence of amikacin, tobramycin, and ciprofloxacin. Also, expression of an efflux pump gene, mexY, was analyzed in selected strains in the presence of amikacin and ferrous. METHODS: Clinical P. aeruginosa strains were isolated from cystic fibrosis patients and minimum inhibitory concentration of amikacin, tobramycin, and ciprofloxacin was determined against all the strains. For each antibiotic, a susceptible and a resistant or an intermediate-resistant strain were selected, encapsulated into alginate beads, and subjected to minimal biofilm eradication concentration (MBEC) test. After determining MBECs, sub-MBEC concentrations (antibiotics at concentrations one level below the determined MBEC) for each antibiotic were selected and used to study the effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of encapsulated strains. Effects of ferrous and amikacin on expression of the efflux pump gene, mexY, was studied on amikacin sensitive and intermediate-resistant strains. One-way ANOVA and t test were used as the statistical tests. RESULTS: According to the results, the supplements had a dose-related effect on decreasing the number of viable cells; maximal effect was noted with ferrous, as ferrous supplementation significantly increased biofilm susceptibility to both ciprofloxacin and amikacin in all strains, and to tobramycin in a resistant strain. Also, treating an amikacin-intermediate strain with amikacin increased the expression of mexY gene, which has a role in P. aeruginosa antibiotic recalcitrance, while treating the same strain with ferrous and amikacin significantly decreased the expression of mexY gene, which was a promising result. CONCLUSIONS: Our results support the possibility of using ferrous and arginine as an adjuvant to enhance the efficacy of conventional antimicrobial therapy of P. aeruginosa infections.

Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial.

Importance: Due to the potential risks of long-term systemic estrogen therapy, many menopausal women are interested in nonhormonal treatments for vasomotor symptoms. Physiologic studies indicate that nitric oxide plays a key role in mediating hot flash-related vasodilation, suggesting that nonhormonal medications that induce nitrate tolerance in the vasculature may offer therapeutic benefit for vasomotor symptoms. Objective: To determine whether uninterrupted administration of transdermal nitroglycerin (NTG) to induce nitrate cross-tolerance decreased the frequency or severity of menopause-related hot flashes. Design, Setting, and Participants: This randomized, double-blinded, placebo-controlled clinical trial included perimenopausal or postmenopausal women reporting 7 or more hot flashes per day who were recruited from northern California by study personnel at a single academic center. Patients were randomized between July 2017 and December 2021, and the trial ended in April 2022 when the last randomized participant completed follow-up. Interventions: Uninterrupted daily use of transdermal NTG (participant-directed dose titration from 0.2-0.6 mg/h) or identical placebo patches. Main Outcome Measures: Validated symptom diaries assessing changes in any hot flash frequency (primary outcome) and moderate-to-severe hot flash frequency over 5 and 12 weeks. Results: Among the 141 randomized participants (70 NTG [49.6%], 71 placebo [50.4%]; 12 [85.8%] Asian, 16 [11.3%] Black or African American, 15 [10.6%] Hispanic or Latina, 3 [2.1%] multiracial, 1 [0.7%] Native Hawaiian or Pacific Islander, and 100 [70.9%] White or Caucasian individuals), a mean (SD) of 10.8 (3.5) hot flashes and 8.4 (3.6) moderate-to-severe hot flashes daily was reported at baseline. Sixty-five participants assigned to NTG (92.9%) and 69 assigned to placebo (97.2%) completed 12-week follow-up (P = .27). Over 5 weeks, the estimated change in any hot flash frequency associated with NTG vs placebo was -0.9 (95% CI, -2.1 to 0.3) episodes per day (P = .10), and change in moderate-to-severe hot flash frequency with NTG vs placebo was -1.1 (95% CI, -2.2 to 0) episodes per day (P = .05). At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes (-0.1 episodes per day; 95% CI, -1.2 to 0.4) or moderate-to-severe hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.7) relative to placebo. In analyses combining 5-week and 12-week data, no significant differences in change in the frequency of any hot flashes (-0.5 episodes per day; 95% CI, -1.6 to 0.6; P = .25) or moderate-to-severe hot flashes (-0.8 episodes per day; 95% CI, -1.9 to 0.2; P = .12) were detected with NTG vs placebo. At 1 week, 47 NTG (67.1%) and 4 placebo participants (5.6%) reported headache (P < .001), but only 1 participant in each group reported headache at 12 weeks. Conclusions and Relevance: This randomized clinical trial found that continuous use of NTG did not result in sustained improvements in hot flash frequency or severity relative to placebo and was associated with more early but not persistent headache. Trial Registration: Clinicaltrials.gov Identifier: NCT02714205.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Phosphodiesterase Type 5 Inhibitors and Oral Nitrates in Male Patients with Ischemic Heart Disease.

PURPOSE OF REVIEW: This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. RECENT FINDINGS: This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.

New lipophilic organic nitrates: candidates for chronic skin disease therapy.

Organic nitrates are widely used, but their chronic efficacy is blunted due to the development of tolerance. The properties of new tolerance free organic nitrates were studied. Their lipophilicity profile and passive diffusion across polydimethylsiloxane membrane and pig ear-skin, and their efficacy in tissue regeneration using HaCaT keratinocytes were evaluated. The permeation results show that these nitrates have a suitable profile for NO topical administration on the skin. Furthermore, the derivatives with higher NO release exerted a pro-healing effect on HaCaT cells. This new class of organic nitrates might be a promising strategy for the chronic treatment of skin pathologies.

Is vitamin C a booster of the effects of dietary nitrate on endothelial function? Physiologic rationale and implications for research.

Endothelial dysfunction (ED) is an early marker of vascular damage linked to the loss of integrity of the endothelial lining and represents a key step in the pathogenesis of atherosclerosis and cardiovascular diseases (CVDs). ED may be reversible, hence the development and testing of effective early interventions could be beneficial for the prevention and treatment of CVDs. Recent studies have demonstrated that the consumption of dietary nitrate (NO3-), an inorganic anion that serves as a substrate for the gas transmitter nitric oxide (NO), can lower blood pressure, improve endothelial function and, in observational studies, reduce the risk for CVD. We hypothesize that the co-consumption of NO3- with vitamin C, which is a potent antioxidant, could enhance the "yield" of NO produced from a given NO3- dose byThis could translate into greater NO-dependent effects on endothelial function (EF) and overall vascular health (than may be experienced with NO3- supplementation alone). This review presents evidence to suggest that the combination of vitamin C and dietary nitrate could represent a promising and effective approach to improve EF and reduce CVD risk, and discuss opportunities for future research.

Moderate doses of dietary nitrate elicit greater effects on blood pressure and endothelial function than a high dose: A 13-week pilot study.

BACKGROUND & AIMS: Few studies have explored the prolonged effects of dietary nitrate on vascular health. This pilot study tested the effects of prolonged consumption (13 weeks) of a range of doses of dietary nitrate (NO3-), provided as beetroot juice (BJ), on blood pressure (BP) and endothelial function in overweight and obese older participants. METHODS AND RESULTS: Sixty-two overweight or obese older participants (60-75 years) were randomized to the following interventions: (1) high NO3- (2) medium NO3-, (3) low NO3-, or (4) placebo. Resting clinic and home BP were measured pre- and post-intervention. Laser Doppler iontophoresis was used to quantify changes in endothelial-dependent and independent microvascular blood flow. RESULTS: This pilot study showed that medium and low doses of NO3- were more effective in lowering resting-clinic SBP (P = 0.04 and, P = 0.03, respectively) than was PL. The lower doses of NO3- also resulted in significant increases in microvascular perfusion (medium, P = 0.02; low, P = 0.002) relative to baseline values. CONCLUSION: These findings indicate that supplementation with medium and low, but not high, doses of NO3- for 13 weeks had positive effects on BP and endothelial function in older overweight and obese adults. These findings require confirmation in larger studies.

Nitrate-rich beet juice intake on cardiovascular performance in response to exercise in postmenopausal women with arterial hypertension: study protocol for a randomized controlled trial.

BACKGROUND: There is no evidence of the use of beetroot juice with a previously recommended dose of nitrate (NO3) (> 300 mg) on the cardiovascular performance during and recovery following exercise in postmenopausal women with systemic arterial hypertension (SAH). METHODS: We will investigate the effects of beetroot juice rich in NO3 acutely (800 mg) and during a week with daily doses (400 mg) on blood pressure, heart rate (HR), cardiac autonomic control, endothelial function, inflammatory, hormonal, and stress biomarkers oxidative stress and enzymes involved in nitric oxide synthesis and mitochondrial regulation, under resting conditions, as well as mediated by submaximal aerobic exercise sessions. Through a randomized, crossover, triple-blind, placebo-controlled clinical trial, 25 physically inactive women with SAH will undergo an acute and 1-week trial, each with two intervention protocols: (1) placebo and (2) beetroot, in which will ingest beet juice with or without NO3 in its composition with a 7-day washout interval. On collection days, exercise will be performed on a treadmill for 40 min at a speed corresponding to 65-70% of VO2peak. The collection of variables (cardiovascular, autonomic, and blood samples for molecular analyses) of the study will take place at rest (135 min after ingestion of the intervention), during exercise (40 min), and in the effort recovery stage (during 60 min) based on previously validated protocols. The collections were arranged so that the measurement of one variable does not interfere with the other and that they have adequate intervals between them. DISCUSSION: The results of this research may help in the real understanding of the nutritional compounds capable of generating safety to the cardiovascular system during physical exercise, especially for women who are aging and who have cardiovascular limitations (e.g., arterial hypertension) to perform physical exercise. Therefore, our results will be able to help specific nutritional recommendations to optimize cardiovascular health. TRIAL REGISTRATION: ClinicalTrials.gov NCT05384340. Registered on May 20, 2022.

[Homeostatic medicine: new strategy and concept of health maintenance as well as diagnosis and treatment of diseases].

Homeostasis is a dynamic balance process of self-regulating. Biological systems remain stable through adapting to changing external conditions to maintain normal life activities. Homeostatic medicine is the science of studying homeostasis of human molecules, cells, organs and the whole body. It is a comprehensive discipline based on maintaining homeostasis to keep human health and assist for diseases prevention and diagnoses. Homeostatic medicine focuses on the whole body and on the role of homeostasis in health and disease, which is expected to provide new ideas and strategies for maintaining health as well as diagnosing and treating diseases. Nitric oxide (NO) plays an important role in the control of multisystem homeostasis. Nitrate is an important substance in regulating NO homeostasis through the nitrate-nitrite-NO pathway. Sialin, nitrate transporter which is located in the cell membrane and cytoplasm, mediates multiple cellular biological functions. The nitrate-nitrite-NO pathway and sialin-mediated biological functions play an important role in the regulation of body homeostasis.