Influence of Dietary Nitrate on Skin Inflammation
Condition: Cardiovascular Diseases; Inflammation; Inflammation; Skin; Inflammatory Response; Nitric Oxide
MeSH terms: Cardiovascular Diseases; Dermatitis; Inflammation
Study type: Interventional
Phase: Phase 1

Summary: 
      This study evaluates the potential anti-inflammatory effects of inorganic dietary nitrate in
      a model of acute inflammation relevant to cardiovascular disease (CVD).

      Green leafy vegetables contain large amounts of inorganic nitrate, and research suggests that
      this nitrate has beneficial effects on the heart and blood vessels. The Ahluwalia Group have
      shown anti-inflammatory benefits of inorganic nitrate in pre-clinical models of CVD, early
      mechanistic studies in healthy volunteers, and in patients with hypertension,
      hypercholesterolaemia and those suffering acute heart attacks that translate to
      cardiovascular benefits. Understanding the mechanism of how this is achieved may open new
      therapeutic options in CVD.

      The Investigators therefore wish to explore whether inorganic nitrate might alter
      inflammatory responses using a blister-model of acute skin inflammation. This study is a
      randomised control trial with parallel limbs where half of patients receive nitrate-rich
      beetroot juice, and the other half a nitrate-deplete placebo beetroot juice.
    

Detailed description: 
      Nitric oxide (NO) is an important substance produced continuously by all blood vessels. It is
      thought to maintain health, in part, by preventing and suppressing inflammatory responses. NO
      is normally generated at the endothelium by a group of important enzymes called nitric oxide
      synthases. However, in chronic inflammatory states such as those seen in cardiovascular
      disease (CVD), the endothelial isoform of the enzyme becomes dysfunctional and produces less
      NO, and the NO that is produced is scavenged by the products of oxidative stress.

      Giving NO back to the blood vessel to mediate its beneficial effects is not straightforward.
      However, the Ahluwalia Group have shown that dietary inorganic nitrate, both as a capsule and
      a dietary intervention with nitrate-rich beetroot juice, has a number of beneficial effects
      in CVD states. This beneficial effect is mediated through it's endogenous conversion from
      nitrate to nitrite in the mouth, and then from nitrite to NO via nitrite reductases within
      the blood vessel. The Investigators have shown benefit of inorganic nitrate in pre-clinical
      models of CVD, early mechanistic studies in healthy volunteers, and anti-inflammatory
      benefits in patients with hypertension, hypercholesterolaemia and those suffering acute heart
      attacks.

      The Investigators wish to prospectively investigate the anti-inflammatory effects of
      inorganic nitrate using a cantharidin-induced blister model of acute inflammation. This
      allows investigation of the innate immune system's response to an acute insult and
      characterise the inflammatory and resolution phases. Cantharidin is commonly used as a
      vesicant in the treatment of plantar verrucae and molluscum contagiosum, and experimentally
      to study the pharmacokinetics of drugs within the interstitial space.

      This will be a double-blind placebo-controlled parallel limb study supplementing 24 healthy
      volunteers with dietary-rich beetroot juice versus nitrate-deplete placebo juice, to
      investigate blister formation, and inflammatory cell recruitment and activation.
    

Intervention name(s): Nitrate-rich Beetroot Juice; Nitrate-deplete Beetroot Juice
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.; See description of placebo juice in "Arms" for comparative information. The beetroot juice contains approximately 100kcal per 100mL of juice, equivalent to a glass of orange juice; the volume of juice per day for the study is 70mL. Volunteers will be informed that an average woman weighing 65kg should not consume more than 2000kcal per day, and an average man of 75kg not more than 2500kcal per day.
Other intervention name(s): Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Double-blind randomised-control parallel two-limb study
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Cardiovascular Disease; Inorganic nitrate; Nitric Oxide; Inflammation