Beet the Cold: The Effect of Inorganic Nitrate Supplementation in Individuals With Raynaud's Phenomenon

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.

Inclusion criteria

• Male or Female, aged 18 years or above.
• Diagnosed with Raynaud's Phenomenon.
• Participant is willing and able to give informed consent for participation in the study.

Exclusion criteria

The participant may not enter the study if ANY of the following apply:

• Patients with significant renal impairment (eGFR<30)
• Uncontrolled hypertension,
• Taking regular organic nitrates, nicorandil, or thiazolidinidiones,
• or any medication which may interfere with data interpretation or safety,
• who have had a myocardial infarction or cerebro-vascular event,
• who smoke,
• or any other serious medical condition which would interfere with data interpretation or safety will be excluded from participation.