Beneficial Effects Of Nitrate Research Articles

Dose-dependent long-term effects of nitrate on lipid profile in male rats

Background. This study aims to investigate the long-term effects of different doses of nitrate on the lipid profile in male rats. Methods. Male Wistar rats (n = 60) were assigned to 6 groups (n = 10 per group). The control group received drinking water, and 5 treatment groups received nitrate at doses of 50, 100, 150, 250, and 500 mg/L for 6 months. Nitric oxide (NO) metabolite levels (NOx) were determined at months 0 and 6. Lipid profile [cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL)] in the serum was measured at months 0, 3, and 6. Results. Nitrate administration for 6 months (at doses of 50, 100, 150, 250, and 500 mg/L) could increase serum NOX levels by 29.5% (P = 0.0115), 39.6% (P = 0.0002), 65.2% (P < 0.0001), 91.4% (P < 0.0001), and 181.6% (P < 0.0001), respectively. Nitrate administration for 6 months (at doses of 50, 100, and 150 mg/L) decreased serum TG [7.8% (P = 0.0508), 7.4% (P = 0.0654), and 8.3% (P = 0.0331)] and cholesterol [12.7% (P = 0.0066), 15.2% (P = 0.0009), and 15.2% (P = 0.0009)] levels. In addition, it increased serum HDL at doses of 50, 100, and 250 mg/L [24.4% (P = 0.0005), 13.9% (P= 0.0910), and 17.5% (P = 0.0172)], while it had no significant effect on serum LDL levels in comparison to the control group. Conclusion. Long-term nitrate administration at low doses (50‒150 mg/L) prevented dyslipidemia (improved lipid profile) in male rats. These beneficial effects of nitrate can be mainly due to increased serum levels of NO metabolites. Practical Implications. These findings imply that long-term nitrate administration at low doses, achieved by consuming a diet containing vegetables, can potentially be utilized to manage dyslipidemia.

Nitrate consumption preserves HFD-induced skeletal muscle mitochondrial ADP sensitivity and lysine acetylation: A potential role for SIRT1

Dietary nitrate supplementation, and the subsequent serial reduction to nitric oxide, has been shown to improve glucose homeostasis in several pre-clinical models of obesity and insulin resistance. While the mechanisms remain poorly defined, the beneficial effects of nitrate appear to be partially dependent on AMPK-mediated signaling events, a central regulator of metabolism and mitochondrial bioenergetics. Since AMPK can activate SIRT1, we aimed to determine if nitrate supplementation (4 mM sodium nitrate via drinking water) improved skeletal muscle mitochondrial bioenergetics and acetylation status in mice fed a high-fat diet (HFD: 60% fat). Consumption of HFD induced whole-body glucose intolerance, and within muscle attenuated insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity (higher apparent Km), submaximal ADP-supported respiration, mitochondrial hydrogen peroxide (mtH2O2) production in the presence of ADP and increased cellular protein carbonylation alongside mitochondrial-specific acetylation. Consumption of nitrate partially preserved glucose tolerance and, within skeletal muscle, normalized insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity, mtH2O2, protein carbonylation and global mitochondrial acetylation status. Nitrate also prevented the HFD-mediated reduction in SIRT1 protein, and interestingly, the positive effects of nitrate ingestion on glucose homeostasis and mitochondrial acetylation levels were abolished in SIRT1 inducible knock-out mice, suggesting SIRT1 is required for the beneficial effects of dietary nitrate. Altogether, dietary nitrate preserves mitochondrial ADP sensitivity and global lysine acetylation in HFD-fed mice, while in the absence of SIRT1, the effects of nitrate on glucose tolerance and mitochondrial acetylation were abrogated.

Independent of mitochondrial respiratory function, dietary nitrate attenuates HFD-induced lipid accumulation and mitochondrial ROS emission within the liver.

The liver is particularly susceptible to the detrimental effects of a high-fat diet (HFD), rapidly developing lipid accumulation and impaired cellular homeostasis. Recently, dietary nitrate has been shown to attenuate HFD-induced whole body glucose intolerance and liver steatosis, however, the underlying mechanism(s) remain poorly defined. In the current study, we investigated the ability of dietary nitrate to minimize possible impairments in liver mitochondrial bioenergetics following 8 wk of HFD (60% fat) in male C57BL/6J mice. Consumption of a HFD caused whole body glucose intolerance (P < 0.0001), and within the liver, increased lipid accumulation (P < 0.0001), mitochondrial-specific reactive oxygen species emission (P = 0.007), and markers of oxidative stress. Remarkably, dietary nitrate attenuated almost all of these pathological responses. Despite the reduction in lipid accumulation and redox stress (reduced TBARS and nitrotyrosine), nitrate did not improve insulin signaling within the liver or whole body pyruvate tolerance (P = 0.313 HFD vs. HFD + nitrate). Moreover, the beneficial effects of nitrate were independent of changes in weight gain, 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) signaling, mitochondrial content, mitochondrial respiratory capacity and ADP sensitivity or antioxidant protein content. Combined, these data suggest nitrate supplementation represents a potential therapeutic strategy to attenuate hepatic lipid accumulation and decrease mitochondrial ROS emission following HFD, processes linked to improvements in whole body glucose tolerance. However, the beneficial effects of nitrate within the liver do not appear to be a result of increased oxidative capacity or mitochondrial substrate sensitivity.NEW & NOTEWORTHY The mechanism(s) for how dietary nitrate prevents high-fat diet (HFD)-induced glucose intolerance remain poorly defined. We show that dietary nitrate attenuates HFD-induced increases in lipid accumulation, mitochondrial-specific reactive oxygen species (ROS) emission, and markers of oxidative stress within the liver. The beneficial effects of nitrate were independent of changes 5' AMP-activated protein kinase signaling, mitochondrial content/respiratory capacity, or lipid-supported respiratory sensitivity. Combined, these data provide potential mechanisms underlying the therapeutic potential of dietary nitrate.

Dietary nitrate attenuated endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: A critical role for NADPH oxidase

Nitric oxide (NO) deficiency and NADPH oxidase plays key roles in endothelial dysfunction and atherosclerotic plaque formation. Recent evidence demonstrates that nitrate-nitrite-NO pathway in vivo exerts beneficial effects upon the cardiovascular system. We aimed to investigate the effects of dietary nitrate on endothelial function and atherosclerosis in apolipoprotein E knockout (ApoE−/-) mice fed a high-fat diet. It was shown that dietary nitrate significantly attenuated aortic endothelial dysfunction and atherosclerosis in ApoE−/- mice. Mechanistic studies revealed that dietary nitrate significantly improved plasma nitrate/nitrite, inhibited vascular NADPH oxidase activity and oxidative stress in ApoE−/- mice, while xanthine oxidoreductase (XOR) expression and activity was enhanced in ApoE−/- mice in comparison with wide type animals. These beneficial effects of nitrate in ApoE−/- mice were abolished by PTIO (NO scavenger) and significantly prevented by febuxostat (XOR inhibitor). In the presence of nitrate, no further effect of apocynin (NADPH oxidase inhibitor) was observed, suggesting NADPH oxidase as a possible target. In vitro, NO donor significantly inhibited NADPH oxidase activity in vascular endothelial cells via the induction of heme oxygenase-1. Altogether, boosting this nitrate-nitrite-NO signaling pathway resulted in the decreases of vascular NADPH oxidase-derived oxidative stress and endothelial dysfunction, and consequently protected ApoE−/- mice against atherosclerosis. These findings may have novel nutritional implications for the preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.

75-OR: Dietary Nitrate and Fecal Transplantation Prevent Cardiac Dysfunction and Attenuate Left Ventricular Mitochondrial Reactive Oxygen Species Emission in High-Fat Diet-Fed Mice

Cardiometabolic diseases are multifactorial conditions involving dysfunction within the left ventricle (LV), adipose tissue (AT), and gut microbiome. Nitrate supplementation has been shown to influence cardiac contractility, mitochondrial function, and microbial populations, effects which require commensal gut bacteria to metabolize nitrate. Therefore, we examined if dietary nitrate and fecal microbial transplant (FMT) from nitrate-fed mice were capable of preventing high fat diet (HFD) induced cardiac abnormalities. Male C57Bl/6N mice were fed a control diet, or HFD (60% fat) in the absence or presence of 4mM sodium nitrate in drinking water for 8 weeks. A further subset of HFD-fed mice were gavaged with feces from HFD+nitrate donors or HFD donors for 3 days at the beginning of week 7, and followed until week 8. Compared to controls, HFD mice presented with ∼25% reduction in end diastolic volume, stroke volume, and cardiac output, in association with an increase in cardiac fibrosis, AT inflammation, and serum lipids. In contrast, dietary nitrate prevented these detrimental effects. The improvement in cardiac function following dietary nitrate was not attributed to changes in LV mitochondrial respiration, however, nitrate prevented the increase in LV mitochondrial reactive oxygen species (ROS) emission associated with HFD. While FMT from HFD+nitrate donors did not influence AT inflammation or cardiac fibrosis, HFD+nitrate FMT decreased serum lipids, LV ROS, and improved cardiac function compared to FMT from HFD-fed donors, without increasing serum nitrate concentrations. Altogether, dietary nitrate prevents the detriments of HFD on cardiac function and LV mitochondrial ROS emission, effects which may not be directly dependent on increasing serum nitrate. Rather, the beneficial effects of nitrate may be linked to changes in the gut microbiome, as FMT from nitrate-fed donors improved LV function. Disclosure H.L. Petrick: None. H. Brunetta: None. A. Kirsh: None. P. Barbeau: None. L.M. Ogilvie: None. J. Simpson: None. J.D. Schertzer: None. G. Holloway: None. Funding Natural Sciences and Engineering Research Council of Canada (400362)

Supplementation of dietary nitrate attenuated oxidative stress and endothelial dysfunction in diabetic vasculature through inhibition of NADPH oxidase

The metabolic disorders in diabetes, which are usually accompanied by oxidative stress and impaired nitric oxide (NO) bioavailability, increase the risk of detrimental cardiovascular complications. Herein, we investigated the therapeutic potential of dietary nitrate, which is found in high content in green leafy vegetables, on vascular oxidative stress and endothelial dysfunction in diabetic mice induced by high-fat diet and streptozotocin injection. Dietary nitrate in drinking water fuelled a nitrate–nitrite–NO pathway, which inhibited vascular oxidative stress, endothelial dysfunction and many features of metabolic syndrome in diabetic mice. These beneficial effects of nitrate on diabetic mice were abolished by PTIO (NO scavenger) treatment and significantly prevented by febuxostat (xanthine oxidoreductase inhibitor), demonstrating the central importance of NO in bioactivation of nitrate. The favorable effects of nitrate were not further influenced by apocynin (NADPH oxidase inhibitor), suggesting NADPH oxidase as a possible target. In high glucose-incubated vascular endothelial cells, NO donor attenuated oxidative stress and endothelial dysfunction via the inhibition of NADPH oxidase, where a heme oxygenase-1 (HO-1)-dependent mechanism was demonstrated for the antioxidant abilities of NO. Altogether, boosting this nitrate–nitrite–NO signaling pathway resulted in the decreases of NADPH oxidase-derived oxidative stress, endothelial dysfunction and metabolic disorders in diabetic vasculature. These findings may have novel implications for the preventive strategy against diabetes-induced vascular dysfunction and associated complications.

Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment.

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications (study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications (study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower (P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min-1·mmHg-1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater (P < 0.05) for nitrate than placebo. The changes in systolic blood pressure (r = -0.60) and FMD (r = -0.48) induced by nitrate were inversely correlated (P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se.NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.

Nitrate, the oral microbiome, and cardiovascular health: a systematic literature review of human and animal studies

Dietary nitrate is an important source of nitric oxide (NO), a molecule critical for cardiovascular health. Nitrate is sequentially reduced to NO through an enterosalivary nitrate-nitrite-NO pathway that involves the oral microbiome. This pathway is considered an important adjunct pathway to the classical l-arginine-NO synthase pathway. The objective of this study was to systematically assess the evidence for dietary nitrate intake and improved cardiovascular health from both human and animal studies. A systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by using key search terms in Medline and EMBASE databases and defined inclusion and exclusion criteria. Thirty-seven articles on humans and 14 articles on animals were included from 12,541 screened references. Data on the effects of dietary nitrate on blood pressure, endothelial function, ischemic reperfusion injury, arterial stiffness, platelet function, and cerebral blood flow in both human and animal models were identified. Beneficial effects of nitrate on vascular health have predominantly been observed in healthy human populations, whereas effects in populations at risk of cardiovascular disease are less clear. Few studies have investigated the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. In animal studies, there is evidence that nitrate improves blood pressure and endothelial function, particularly in animal models with reduced NO bioavailability. Nitrate dose seems to be a critical factor because there is evidence of cross-talk between the 2 pathways of NO production. Evidence for a beneficial effect in humans at risk of cardiovascular disease is limited. Furthermore, there is a need to investigate the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. Further animal studies are required to elucidate the mechanisms behind the observed effects.

Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study.

BackgroundNitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease (CVD) and all‐cause mortality.Methods and ResultsWe assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography–mass spectrometry and evaluated its association with all‐cause mortality and incident CVD. On follow‐up (median 17.3 years), 775 participants died and 522 developed new‐onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log‐nitrate 1.21; 95% confidence interval, 1.04–1.40 [P=0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00–1.35 [P=0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable‐adjusted hazard ratio per unit increase log‐nitrate 1.08; 95% confidence interval, 0.89–1.31 [P=0.42]).ConclusionsIn our prospective community‐based investigation, a higher plasma nitrate concentration was associated with all‐cause mortality but not with incident CVD. The association of nitrate with mortality may at least in part be attributable to its association with renal function.

Role of nutrition in performance enhancement and postexercise recovery.

A number of factors contribute to success in sport, and diet is a key component. An athlete’s dietary requirements depend on several aspects, including the sport, the athlete’s goals, the environment, and practical issues. The importance of individualized dietary advice has been increasingly recognized, including day-to-day dietary advice and specific advice before, during, and after training and/or competition. Athletes use a range of dietary strategies to improve performance, with maximizing glycogen stores a key strategy for many. Carbohydrate intake during exercise maintains high levels of carbohydrate oxidation, prevents hypoglycemia, and has a positive effect on the central nervous system. Recent research has focused on athletes training with low carbohydrate availability to enhance metabolic adaptations, but whether this leads to an improvement in performance is unclear. The benefits of protein intake throughout the day following exercise are now well recognized. Athletes should aim to maintain adequate levels of hydration, and they should minimize fluid losses during exercise to no more than 2% of their body weight. Supplement use is widespread in athletes, with recent interest in the beneficial effects of nitrate, beta-alanine, and vitamin D on performance. However, an unregulated supplement industry and inadvertent contamination of supplements with banned substances increases the risk of a positive doping result. Although the availability of nutrition information for athletes varies, athletes will benefit from the advice of a registered dietician or nutritionist.

Nitrate in vegetables and their impact on human health. A review

Vegetables are the major source of dietary nitrate, with wide variations in nitrate content. The presence of nitrate in vegetables is often associated with harmful effects on human health, i.e. with toxic effects of methaemoglobinaemia and the possibility of causing an endogenous formation of carcinogenic N-nitroso compounds. However, it is also associated with beneficial health effects, since nitrate represent an important alternative pathway to bioactive NO and its important physiological roles in vascular and immune function. In this review the concentrations of nitrate in different vegetables from different countries are given. Furthermore, the reasons for the different contents of nitrate in vegetables, the daily intakes and comparisons to the acceptable daily intake (ADI) values, legislation, metabolism and toxicology of nitrate are described as well as harmful and beneficial effects of nitrate on human health.

The oral bioavailability of nitrate from nitrate-rich vegetables in humans

High dietary nitrate intake may pose a risk to human health. Since up to 80–85% of dietary nitrate intake comes from vegetables, the aim of this study was to determine the absolute bioavailability of nitrate from three nitrate-rich vegetables. In an open, four-way cross-over, single dose study, 12 human subjects underwent the following treatments: (1) intravenous infusion of 500 mg sodium nitrate, (2) oral administration of 300 g cooked spinach, (3) oral administration of 300 g raw lettuce, and (4) oral administration of 300 g cooked beetroot. The wash-out period between treatments was at least 6 days. Plasma samples were analysed to assess the nitrate and nitrite concentrations, and pharmacokinetic parameters were calculated. The bioavailability of nitrate was 98 ± 12% from cooked spinach, 114 ± 14% from raw lettuce and 106 ± 15% from cooked beetroot. There was no significant increase in plasma nitrite concentrations. This study shows that nitrate from vegetables, whether cooked or uncooked, is absorbed very effectively, resulting in an absolute nitrate bioavailability of around 100%. Thus, reducing the amount of nitrate in vegetables can be an effective measure to lower the systemic nitrate exposure of the general population. However, other aspects, such as the costs to produce vegetables with a low nitrate content and the possible beneficial effects of nitrate in vegetables, need to be considered when evaluating the usefulness of such a measure.

Long-Term Nitrate Use in Acute Myocardial Infarction (The Heart Institute of Japan, Department of Cardiology Nitrate Evaluation Program)

The lack of any randomized controlled trials demonstrating a beneficial effect of nitrates for the secondary prevention of coronary artery disease leads to a negative recommendation in current practice guidelines. The aim of the present study was to examine the efficacy of nitrate therapy for the treatment of acute myocardial infarction (AMI) in the contemporary revascularization era. Of 2,736 consecutive patients with AMI (1,677 on nitrate therapy and 1,059 control patients not receiving nitrates), 1,766 patients were matched according to a propensity score (883 receiving nitrates and 883 control subjects). Before propensity score matching, the patients treated with nitrates were significantly older, had a higher Killip class, and underwent less aggressive revascularization and less modern pharmacotherapy compared with the patients who were not given nitrates. A total of 117 patients (11.0%) died in the control group and 317 patients (18.9%) in the nitrate group (hazard ratio, 1.70; 95% CI, 1.38-2.10; P < 0.001) during a 5-year follow-up period. In contrast, among propensity score-matched patients, 110 patients (12.5%) died in the control group and 126 patients died (14.3%) in the nitrate group (hazard ratio, 1.06; 95% CI 0.82-1.36, P = 0.678). The 1-, 3- and 5-year cumulative mortality rates (Kaplan-Meier method) were respectively 4.5%, 9.8%, and 14.1% in the control group versus 5.2%, 9.8%, and 14.8% in the nitrate group. There were also no statistical or clinical differences between the two matched groups with regard to the other endpoints assessed. Our results suggest that nitrate therapy does not increase mortality and cardiac events in AMI patients. Our results differ from those of previous observational studies, suggesting that new prospective randomized clinical trials are needed in the current revascularization era.

Nitrate accumulation in plants, factors affecting the process, and human health implications. A review

Leafy vegetables occupy a very important place in the human diet, but unfortunately constitute a group of foods which contributes maximally to nitrate consumption by living beings. Under excessive application of nitrogen fertilizer, these vegetables can accumulate high levels of nitrate and, upon being consumed by living beings, pose serious health hazards. Therefore, efforts are warranted to minimize the accumulation of nitrate in leafy vegetables and its ingestion by human beings. This review focuses on (i) the contribution of vegetables towards dietary nitrate intake by humans, (ii) the nutritional, environmental and physiological factors affecting nitrate accumulation in plants, (iii) the harmful and beneficial effects of nitrate on human health, and (iv) the strategies that may be followed to minimize the nitrate content in plants and its subsequent consumption by human beings. The risk to human health due to nitrate consumption may be minimized by harvesting vegetables at noon, removal of organs rich in nitrate content and cooking of vegetables in water with a low nitrate content. The European Commission Regulation No. 1822/2005 needs to be followed in order to ensure safe levels of nitrate in plants for human consumption.

Oral nitrates: more than symptomatic therapy in coronary artery disease?

The predominant venodilator properties of the nitrates and their augmentation of collateral coronary blood flow to the ischemic myocardium endows them with some ideal characteristics for treating myocardial ischemic syndromes. Additional efficacy stems from the ability of the nitrates to replenish the deficient endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in patients with coronary heart disease and also to inhibit platelet aggregation. In stable angina pectoris, the antianginal and antiischemic effects of oral nitrates are well established. Continuous administration of nitrates may lead to tolerance of their clinical efficacy. Recent studies, however, have demonstrated that when used in recommended doses, tolerance can be avoided during long-term treatment with oral nitrates without provocation of anginal attacks during periods of low nitrate levels at night and early hours of the morning. Thus, prolonged treatment with an asymmetric twice-daily regimen of immediate-release isosorbide-5-mononitrate in patients with stable angina pectoris does not give rise to clinical tolerance, prolongs exercise duration, and delays the onset of myocardial ischemia. In unstable angina pectoris, nitrates rapidly relieve chest pain and ameliorate the electrocardiographic signs of myocardial ischemia. In patients with acute myocardial infarction, early treatment with nitrates prevents left ventricular dilatation, improves pumping function, and reduces the risk of ventricular arrhythmias. In patients with chronic heart failure, oral nitrates improve exercise tolerance and, when given in combination with the systemic arterial dilator hydralazine, extend survival. Meta-analysis of published studies has demonstrated that both intravenous and oral nitrates reduced infarct size and morbidity and mortality in patients with acute myocardial infarction. In the ISIS 4 post-infarction study, isosorbide-5-mononitrate 60 mg once daily was not superior to placebo in reducing mortality risk. However, in the GISSI 3 study, the combination of nitrates with an angiotensin-converting enzyme (ACE) inhibitor reduced mortality risks by 17% in patients with acute myocardial infarction. In both the ISIS 4 and GISSI 3 studies, 62% and 57% of the patients in the placebo and control groups, respectively, were treated with nitrates for control of rest angina, myocardial ischemia, and or left ventricular failure symptoms, and this widespread use of open-label nitrates in the control groups may have diluted the true beneficial effects of nitrates in both studies. Taken together, these many studies with oral nitrate treatment in coronary heart disease and heart failure clearly emphasize that these drugs are safe and play more than a symptomatic role in the management of patients with acute and chronic ischemic syndromes due to coronary artery disease.

Beneficial effect of nitrates on myocardial glucose utilization in unstable angina pectoris

Myocardial uptake of the glucose analog F-18-2-fluoro-2-deoxy-D-glucose (FDG) was assessed by positron emission tomography in 6 normal volunteers, 7 patients with chronic stable angina and 22 patients with unstable angina at rest in fasting conditions. Regional myocardial perfusion was assessed by rubidium-82. The study was repeated a few days later after intravenous infusion of isosorbide dinitrate. FDG uptake was similar in control subjects and patients with stable angina (0.023 ± 0.032 vs 0.012 ± 0.008 mol/ml/min, p <0.42) but was about 4-fold higher on the average in patients with unstable angina (0.084 ± 0.047, p <0.01). The severity of coronary obstructions in stable and unstable angina patients was similar. The increased uptake involved the whole heart, including areas not distal to critically stenosed vessels; it was not associated with reduced myocardial perfusion and was not related to a recent episode of transient ischemia as assessed by symptoms and by Holter monitoring. After continuous infusion of nitrates, FDG uptake was consistently and significantly reduced toward normal levels both in areas perfused by critically stenosed coronary arteries and by noncriticaliy stenosed vessels.

Promise and Perils of Drugs in Stable Angina: Nitrates

Venous pooling and after-load reduction are commonly believed to be the most important mechanism for the anti-anginal activity of nitrates. Recent studies were able to demonstrate a beneficial effect of nitrates on the coronary vasomotor tone. Very small doses of nitroglycerin increase the diameter of epicardial vessels and, most importantly, the diameter of the arteriosclerotic lesion itself. The effectiveness of nitroglycerin patches may also be related to the coronary component of the mechanism. Controversy exists with regard to the long-term effect of nitrates since some authors have demonstrated nitrate tolerance. In clinical practice tolerance has not created major problems so far but further studies are needed to resolve the conflicting evidence produced by different groups of workers.

Epinephrine Reaction Treated With Nitroglycerin

To the Editor:— Although serious reactions from epinephrine are rare, the use of large doses or the accidental injection of epinephrine intravenously may cause excessive increase in blood pressure with possible cerebral hemorrhage, acute pulmonary edema, and ventricular arrhythmia. 1,2 It is well known that rapidly acting vasodilators, such as nitrites, may counteract the marked pressor effects induced by epinephrine. 1 However, the beneficial effect of nitrates upon ventricular arrhythmias induced by epinephrine is not as well appreciated. The following communication describes a severe epinephrine reaction manifested by marked rise of blood pressure and ventricular arrhythmia which responded favorably to nitroglycerin. Report of a Case:— A 45-year-old Negro man was brought to the University of Maryland Hospital accident room on March 22, 1967, complaining of pain in the left wrist after he had fallen on the ice. A roentgenogram revealed a fracture at the base of the first metacarpal bone.