Elsevier

Nitric Oxide

Volume 24, Issue 1, 1 January 2011, Pages 34-42
Nitric Oxide

Acute effect of a high nitrate diet on brain perfusion in older adults

https://doi.org/10.1016/j.niox.2010.10.002Get rights and content

Abstract

Aims

Poor blood flow and hypoxia/ischemia contribute to many disease states and may also be a factor in the decline of physical and cognitive function in aging. Nitrite has been discovered to be a vasodilator that is preferentially harnessed in hypoxia. Thus, both infused and inhaled nitrite are being studied as therapeutic agents for a variety of diseases. In addition, nitrite derived from nitrate in the diet has been shown to decrease blood pressure and improve exercise performance. Thus, dietary nitrate may also be important when increased blood flow in hypoxic or ischemic areas is indicated. These conditions could include age-associated dementia and cognitive decline. The goal of this study was to determine if dietary nitrate would increase cerebral blood flow in older adults.

Methods and results

In this investigation we administered a high vs. low nitrate diet to older adults (74.7 ± 6.9 years) and measured cerebral perfusion using arterial spin labeling magnetic resonance imaging. We found that the high nitrate diet did not alter global cerebral perfusion, but did lead to increased regional cerebral perfusion in frontal lobe white matter, especially between the dorsolateral prefrontal cortex and anterior cingulate cortex.

Conclusion

These results suggest that dietary nitrate may be useful in improving regional brain perfusion in older adults in critical brain areas known to be involved in executive functioning.

Introduction

Until recently, nitrite was thought to be relatively inert biologically [1]. However, nitrite infusions leading to slightly supraphysiologic levels of plasma nitrite, from 180 nM at baseline to 2600 nM, elevated forearm blood flow and was associated with nitric oxide (NO) formation [2]. Further research showed that a smaller rise in plasma nitrite to only 350 nM also increased forearm blood flow [3]. Levels of nitrite in plasma that are shown to improve blood flow can be achieved by consuming foods high in nitrate [4]. Once ingested, nitrate is absorbed from the upper part of the intestine, and transported via plasma into salivary glands where it is concentrated and released into saliva. Nitrate is subsequently reduced to nitrite by symbiotic, oral bacteria. The nitrite is swallowed and ultimately absorbed from the intestine into the circulatory system [4], [5]. Several groups have shown that ingesting diet sources high in nitrate leads to substantial increases in plasma nitrite [6], [7], [8], [9]. This conversion of nitrate to nitrite can be eliminated when volunteers either expectorate or use mouthwash which kills oral bacteria that are key to the conversion process [6], [8]. Physiologic effects from increasing dietary nitrate and plasma nitrite include reduction in blood pressure [6], [8], improvement in intestinal health [10], and increases in exercise performance [9] which are all attributed to the further reduction of nitrite to NO. Interestingly, nitrite is being investigated for use in a variety of conditions, including ischemic-reperfusion injury, pulmonary hypertension, stroke, sickle cell disease, and gastric diseases [5], [11]. A major feature of nitrite’s ability to increase blood flow is that it acts preferentially in hypoxic conditions, allowing nitrite to increase blood flow precisely in the areas where it is needed most [2], [12], [13]. We hypothesized that we could use this feature to increase cerebral blood flow in older adults.

As the average age in the United States continues to rise, there has been increasing interest in gaining a better understanding of the aging brain and the neurological morbidities that accompany aging. Cognitive decline in general and dementia in particular, are sources of morbidity and dependency for older adults. These conditions also place an enormous burden on the family and society. It has been shown that diminished blood flow to the brain contributes to cognitive impairment [14]. In addition, from the Rotterdam study, it has been shown that cerebral hypoperfusion precedes and probably contributes to the onset of clinical dementia [15]. Moreover, diminished cerebral blood flow has been linked to poorer cognition, such as a reduction in information processing speed, and to dementia [16], [17]. A ubiquitous finding in neurocognitive disorders associated with aging is the so-called “white matter hyperintensity” (WMH). Chronic ischemia appears to be the fundamental process that leads to WMHs, often referred to as leukoaraiosis. Several underlying mechanisms have been shown to contribute to this chronic ischemic state, including abnormal arterioles, capillaries and venules, and increased tortuosity of arterioles as we age [18], [19], [20]. Chronic ischemia in the white matter appears to be the complex endgame leading to the WMHs and is associated with cognitive decline [21]. In particular, age-related white matter degeneration has been linked to poor executive functioning as assessed by measures of working memory [22], [23] dichotic listening [24], task switching [25] and episodic retrieval [26].

The current analyses are on 2 separate studies. The first was a preliminary study that tested the time course of plasma nitrate and nitrite levels over a 3-h period following consumption of a high nitrate breakfast, which included beetroot juice. This provided us with a target time for measuring cerebral blood flow in the subsequent study based on the peak level achieved and kinetics of the plasma nitrate and nitrite concentrations. The subsequent and primary study examined in a within subject design the effect of two levels of dietary nitrate (high vs. low) over a 24-h feeding period on acute changes in cerebral blood flow in older adults as measured by magnetic resonance (MR) imaging. Each person was provided both dietary conditions in a randomized order on separate days and blood flow was assessed with each diet. The hypothesis for the primary study was that a diet high in nitrate containing foods and beverages would produce changes in cerebral blood flow in key and critical areas of the brain, principally those associated with executive function, compared to a diet of foods that are low in nitrate. The fact that nitrite-based increases in blood flow targets areas of hypoxia [2], [12], [13], [27], [28], [29] supports the hypothesis that increasing plasma nitrite will increase cerebral brain perfusion in these areas where it is needed most.

Section snippets

Subject description

Subject selection for both studies followed the same criteria with an age cutoff of ⩾70 years old. In the preliminary study, a total of 5 individuals were recruited, and the primary aim for the larger trial was addressed by recruiting a total of 16 older adults to undergo both a high nitrate and a low nitrate dietary intervention as approved by the Institutional Review Board at Wake Forest University. The investigations conformed to the principles outlined in the Declaration of Helsinki. A phone

Results

For both studies presented, the beetroot beverage and diets were generally well-tolerated by participants. The common expected side effects of red stools and urine associated with drinking beetroot juice (beeturia) were experienced and reported. One individual in the perfusion study was excluded from the analysis as they refused to drink the beetroot juice on day 2 of the high nitrate diet. No other symptoms, such as dizziness, orthostatic hypotension, or headaches were reported by

Discussion

In a study led by Gladwin in 2003, it was shown that slightly supraphysiological amounts of infused nitrite (going from 180 nM at baseline to 2600 nM after infusion) led to increased forearm blood flow [2]. More recently, the Gladwin lab showed that infusion of nitrite to achieve a level of only 350 nM results in increased forearm blood flow [3]. Others have since confirmed that nitrite acts as a vasodilator in various tissues and that its activity is heightened in hypoxia [36], [37], [38], [39],

Conclusions

We have shown, as previously demonstrated in younger adults, that consumption of a high nitrate diet results in substantial increases in plasma nitrite in older adults. The increase in plasma nitrite and nitrate is sustained, even after overnight fast. Generally, we hypothesize that dietary nitrate may be beneficial in compensating for age-related endothelial dysfunction and associated pathology. In this study we focused on cerebral blood flow and found that perfusion increased in frontal lobe

Conflicts of interest

Dr. Kim-Shapiro is listed as a co-author on a patent application entitled “Use of nitrite salts for the treatment of cardiovascular conditions”.

Funding

This work was supported by the Translational Science Center on the Reynolda Campus at Wake Forest University, The Science Research fund of Wake Forest University, and National Institutes of Health [Grant Nos. HL058091; HL62198].

Acknowledgments

We thank Erin Reddan, Alesia Goodman, Rebecca Patten, Rudayna Chanouha, Kati Gigler, Andrea Worsham, Sara Turner, Aasha Anderson, and Michael Font for technical assistance.

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