Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content.Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics.Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD).Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment.Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752.

Abstract-Elevation of circulating nitrite (NO 2 − ) levels causes vasodilatation and lowers blood pressure in healthy volunteers. Whether these effects and the underpinning mechanisms persist in hypertension is unknown. Therefore, we investigated the consequences of systemic nitrite elevation in spontaneously hypertensive rats and conducted proofof-principle studies in patients. Nitrite caused dose-dependent blood pressure-lowering that was profoundly enhanced in spontaneously hypertensive rats versus normotensive Wistar Kyoto controls. This effect was virtually abolished by the xanthine oxidoreductase (XOR) inhibitor, allopurinol, and associated with hypertension-specific XOR-dependent nitrite reductase activity localized to the erythrocyte but not the blood vessel wall. To determine whether these pathways translate to human hypertension, we investigated the effects of elevation of circulating nitrite levels in 15 drug naïve grade 1 hypertensives. To elevate nitrite, we used a dose of dietary nitrate (≈3.5 mmol) that elevated nitrite levels ≈1.5-fold (P<0.01); a rise shown previously to exert no significant blood pressure-lowering effects in normotensives. This dose caused substantial reductions in systolic (≈12 mm Hg) and diastolic blood pressures (P<0.001) and pulse wave velocity (P<0.05); effects associated with elevations in erythrocytic XOR expression and XOR-dependent nitrite reductase activity.

Highlights► Inorganic nitrate supplementation does not alter endothelial function in healthy volunteers. ► Despite this, there was a reduction in blood pressure and improvement in arterial compliance. ► Improvements in vascular function are likely to contribute to the beneficial effects of inorganic nitrate on blood pressure.

Ingestion of vegetables rich in inorganic nitrate has emerged as an effective method, via the formation of a nitrite intermediate, for acutely elevating vascular NO levels. As such a number of beneficial effects of dietary nitrate ingestion have been demonstrated including the suggestion that platelet reactivity is reduced. In this study we investigated whether inorganic nitrate supplementation might also reduce platelet reactivity in healthy volunteers and have determined the mechanisms involved in the effects seen. We conducted two randomised crossover studies each in 24 (12 of each sex) healthy subjects assessing the acute effects of dietary nitrate (250 ml beetroot juice) or potassium nitrate capsules (KNO3, 8 mmol) vs placebo control on platelet reactivity. Inorganic nitrate ingested either from a dietary source or via supplementation raised circulating nitrate and nitrite levels in both sexes and attenuated ex vivo platelet aggregation responses to ADP and, albeit to a lesser extent, collagen but not epinephrine in male but not female volunteers. These inhibitory effects were associated with a reduced platelet P-selectin expression and elevated platelet cGMP levels. In addition, we show that nitrite reduction to NO occurs at the level of the erythrocyte and not the platelet. In summary, our results demonstrate that inorganic nitrate ingestion, whether via the diet or through supplementation, causes a modest decrease in platelet reactivity in healthy males but not females. Our studies provide strong support for further clinical trials investigating the potential of dietary nitrate as an adjunct to current antiplatelet therapies to prevent atherothrombotic complications. Moreover, our observations highlight a previously unknown sexual dimorphism in platelet reactivity to NO and intimate a greater dependence of males on the NO-soluble guanylate cyclase pathway in limiting thrombotic potential.

Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

Background Pulmonary hypertension (PH) is a multi-factorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO3−) and nitrite (NO2−) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity. Methods & Results Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular re-modeling, in wild-type mice exposed to 3 weeks hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma & lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase (eNOS) or treated with the xanthine oxidoreductase (XOR) inhibitor allopurinol. Conclusions These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the RVH characteristic of PH. This favorable pharmacodynamic profile is dependent on eNOS and XOR -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (i.e. dietary nitrate/nitrite supplementation) represents a viable, orally-active therapy for PH.

In this review, we discuss the evidence supporting a role for XOR as a nitrite reductase while focusing particularly on its function in hypertension. In addition, we discuss the potential merit in exploiting this activity of XOR in the therapeutics of hypertension.

SummaryThe quality of donor organs will determine the quality of life for the recipient and the importance of optimal management of the multi-organ donor is that the organs may benejit up to jive, critically ill, patients. The basic principle is to maintain suficient preload to minimise the need for inotropic support and it is recommended that all multiple organ donors should have central venous and arterial pressure monitoring in addition to adequate venous access. The importance of the choice offluid for volume expansion and the management of the hormonal disturbances which follow brain death are considered. Key wordsTransplantation; heart, heart-lung. Management; donors.Management of the potential donor referred for organ retrieval presents an unfamiliar clinical situation for some intensive care and anaesthetic staff. Those responsible for the care of donors in the peri-operative period may have limited experience of the problems that may arise, both as a result of the pathophysiological changes that accompany brainstem death and of the organ retrieval procedure. Heart and heart-lung transplantation is a means of treatment for end-stage cardiopulmonary disease and it is important that organs are not lost from the limited supply as a result of inadvertent mismanagement before and during organ retrieval. Medical and nursing staff may tend to devote their skill and attention to other patients, once a patient is declared brainstem dead. The donor thus undergoes two periods of intense medical activity punctuated by a period of relative neglect: the first after admission to Intensive Care Unit before declaration of brainstem death in a bid to preserve life, the second during the organ retrieval operation to maintain sufficient stability to allow satisfactory harvesting. Between these two periods, however, little attention may be focused on maintaining the donor patient in an optimum state. It is during this time that damage to organs may occur. Potential causes of cardiopulmonary dysfunction in donorsIrreversible cerebral injury in the majority of donors is the result of trauma or catastrophic intracranial haemorrhage.',Z Functional deterioration may occur as a part of the natural history of massive cerebral injury and from iatrogenic causes, although donor heart and lungs are, by implication, free of serious intrinsic disease. Death of the brainstem, in the natural course of events, is followed by a steady decline in cardiovascular stability. Progressive vasodilatation occurs and the hypotension that this produces may be compounded by impairment of myocardial performance. Marked impairment of ventricular function has been demonstrated in animal models of brainstem death and in brainstem-dead patient^.^.^ Electrocardiographic and enzyme changes indicative of myocardial damage occur in association with subarachnoid haemorrhage and traumatic head injury in patients with no history of myocardial p a t h o l~g y .~.~ Moreover 30% of donor hearts biopsied before removal show evidence of cellular degeneration; this corr...