Raynaud Phenomenon Clinical Trial
Official title:
Beet the Cold: The Effect of Inorganic Nitrate Supplementation on Peripheral Blood Flow and Pain in Individuals With Raynaud's Phenomenon. A Pilot, Double-blind, Placebo Controlled, Randomised Crossover Trial
Individuals with Raynaud's phenomenon often experience episodes of reduced blood flow to
their fingers and toes during times of stress or cold exposure, causing significant
discomfort and pain. Typically, treatment for these individuals involves using drugs like
Glyceryl Trinitrate (GTN), which increases blood flow to the fingers and toes by increasing a
substance called nitric oxide in the blood. Unfortunately, repeated use of these drugs
increases tolerance to them, meaning higher doses are required to produce the same effect.
However, increasing the dose can cause more side effects like headaches, and is therefore not
considered an ideal long-term therapy.
Leafy green vegetables, especially beetroot, contain high amounts of nitrate and are
beneficial to blood vessel health, since nitrate from the diet can also be turned into the
important blood vessel relaxer, nitric oxide. Unlike GTN, people don't appear to develop a
tolerance to dietary nitrate or experience negative side effects.
Therefore, this study aims to see if short and longer term beetroot juice supplementation can
improve blood flow to the hands and feet in individuals with Raynaud's phenomenon, as well as
reduce their pain. This study will tell us how many people are needed for a definitive trial
investigating whether beetroot juice can help treat Raynaud's phenomenon.
Raynaud's phenomenon can cause significant discomfort and pain to individuals. Dietary
nitrate appears to offer a simple, low cost means of improving blood flow to the hands and
feet which should reduce both the discomfort and pain experienced characterising this
condition. This study will advance our understanding of the causes of Raynaud's phenomenon,
specifically the role that the nitrate-nitrite-nitric oxide pathway might play in changing
Raynaud's phenomenon symptoms and identifying targets for intervention.
Raynaud's phenomenon (RP) is characterised by a recurrent transient vasospasm of the fingers
or toes in response to a cold or stressful stimulus. Nitric oxide (NO•) is a known
vasodilator and NO• donors, such as Glyceryl Trinitrate (GTN), improve blood flow in patients
with RP and in cold sensitive individuals (Figure 1, see accompanying document). However,
individuals develop a tolerance to GTN and show diminishing vasodilatory effects with chronic
treatment. In addition, the deleterious side effects such as headaches means that organic
nitrates (i.e. GTN and isosorbide mononitrate) are not optimal longterm therapies for RP.
Alternative treatments therefore, warrant further investigation.
Diets rich in fruit and vegetables has been shown to be effective in reducing blood pressure.
In addition, it lowers the risk of morbidity and mortality from cardiovascular disease and
are thought to be beneficial to cardiovascular health due to their vasodilatory effects. As
diet exhibits such tremendous intra- and inter-individual variation, elucidating which
components of such a diet are responsible for this effect is difficult. There is a growing
weight of evidence from both human and animal studies that nitrate and nitrite derived from
the diet can serve as a source for nitric oxide (NO; please see below), particularly where it
is deficient. Indeed, the greatest protective effect on cardiovascular disease is to be found
in those diets with the greatest consumption of green leafy and or cruciferous vegetables
which typically have high nitrate content.
NO is produced in the body in two ways. The first requires the availability the amino acid
L-arginine, molecular oxygen, and families of enzymes, the nitric oxide synthases (NOS); that
is the NOS pathway. The second pathway is independent of NOS pathway and involves the
stepwise enzymatic and chemical reduction of inorganic nitrate to nitrite. A major source of
nitrite in humans is the reduction of dietary nitrate by facultative anaerobic bacteria in
the mouth. The remaining nitrite is then absorbed into the circulation where it acts as a
storage pool for subsequent NO• production, which is expedited in hypoxaemia.
Localised hypoxemia such as that observed in the digital vasculature of individuals with RP
is a potential therapeutic target for dietary nitrate supplementation. In contrast to organic
nitrates (GTN), inorganic nitrate (in the form of beetroot juice) does not cause the same
negative side effects or demonstrate tachyphylaxis whilst it does notable improve skin blood
flow, microvascular function and lower blood pressure (BP) in healthy individuals and chronic
conditions such as hypertension, peripheral arterial disease, heart failure and chronic
obstructive pulmonary disease. Thus concentrated beetroot juice (CBJ) may offer an
inexpensive, safe and potentially effective intervention to improve the pain and reduced
peripheral blood flow characterising individuals with RP.
RP can cause significant discomfort and pain to individuals during a vasospasm. Dietary
nitrate appears to offer a simple, low cost means of modifying blood flow to the peripheries
and, ultimately, reducing both the discomfort and pain experienced by individuals with RP.
This study will also advance our understanding of the aetiology and pathophysiology of RP,
specifically the role that the nitrate-nitrite-nitric oxide pathway might play in modulating
RP symptoms. An understanding of the effects of concentrated beetroot juice on microvascular
blood flow and pain may lead to a range of simple, low cost and effective therapeutic
interventions to prevent and treat episodes of RP.
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