L-citrulline Supplementation & Cold Exposure
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Cardiovascular disease (CVD) is considered the primary cause of death in the developed world.
      Large scale epidemiological studies indicate that prevalence of hypertension along with
      adverse cardiovascular events peak during the winter months. Moreover, during the winter
      months outdoor activities and physical stressors such as exercise have been associated with
      higher cardiovascular mortality when compared to other periods of the year. Although low
      environmental temperatures have been implicated as the triggering factor for cardiovascular
      complications, the mechanisms on how cold exposure increase cardiovascular morbidity and
      mortality remain to be elucidated. However, new research suggests that cold exposure may
      induce increases in cardiac sympathetic activity, endothelial damage and increased arterial
      stiffness of central arteries. Cardiovascular drugs including antihypertensive
      pharmacological agents seem to be inefficient to provide appropriate therapeutic effects
      during cold exposure. Therefore, it is imperative to propose alternative non-pharmacological
      therapies intended to prevent the detrimental effects of low environmental temperatures on
      cardiovascular function. Recently, oral supplementation of the amino acid L-citrulline has
      been proposed as an effective therapeutic adjuvant for the treatment of hypertension.
      L-citrulline is known to enhance the bioavailability of L-arginine levels and increase
      endothelial nitric oxide (NO) production, one of the main modulators of vascular tone and
      blood pressure (BP). L-citrulline supplementation has been shown to increase endothelial
      function, reduce BP, and ameliorate endothelial oxidative damage without any adverse effects.
      Our group has demonstrated that L-citrulline supplementation attenuates the BP response to
      cold exposure (the cold pressor test, CPT). These studies suggest that L-citrulline
      supplementation may be a feasible therapeutic aid in order to prevent cardiovascular
      complications associated with cold exposure. However the potential cardioprotective effects
      of L-citrulline supplementation during cold exposure with exercise have yet to be evaluated.
      It is hypothesized that L-citrulline supplementation would reduce arterial stiffness and
      blood pressure (BP) responses to physiological stress (cold exposure). This study may lead to
      the development of an adjunct therapy for the prevention and management of cardiovascular
      adverse events that are particularly increased during the winter months.
    

Detailed description: 
      The specific aims of the study are:

      AIM 1: To determine the acute effects of cold exposure and isometric exercise, on
      cardiovascular hemodynamics and autonomic regulation. The working hypothesis is that the
      combination of cold exposure with isometric hand grip (IHG) exercise would evoke a greater
      acute increase in arterial stiffness, wave reflection, arterial BP and sympathetic activity
      than cold exposure or IHG alone. In order to test this hypothesis, the investigators will use
      an environmental chamber at a temperature of 4oC to perform non-invasive measurements of
      arterial stiffness (carotid-femoral, femoral-ankle, and brachial-ankle pulse wave velocity
      [PWV]), pulse wave analysis (aortic BP and augmentation index [AIx]) using applanation
      tonometry of the radial artery. In addition, the investigators will use continuous
      beat-by-beat digital BP, power spectral analysis of heart rate variability and blood pressure
      variability, and spontaneous BRS to evaluate autonomic function during cold exposure.

      AIM 2: To examine the effects of L-citrulline supplementation on cardiovascular hemodynamics,
      autonomic regulation and endothelial function. The investigators will test the working
      hypothesis that L-citrulline supplementation for 14 days will attenuate the cardiovascular
      responses to physiological stress. The investigators will perform the same procedures
      previously specified in AIM I.

      AIM 3: To determine the acute and chronic L-citrulline supplementation on endothelial
      function by measuring flow-mediated vasodilation, vasoactive substances, and Endothelial
      Progenitor Cells (EPCs). This aim will examine the working hypothesis L-citrulline will
      result in greater circulating levels of vasodilatory substances including nitric oxide,
      prostacyclin, and EPCs whereas vasoconstrictor substances endothelin-I (ET-1) will decrease.
      This aim will be tested by measuring serum levels of these substances before and immediately
      after the session at baseline and 7 days after the intervention.

      Description of the study Forty individuals (20 men and 20 women) 18-35 years of age with
      normal resting BP (< 140/90 mmHg) will be enrolled in this study. Subjects should not be
      smokers, L-citrulline users or regular exercisers (defined as more than 120 min per week) in
      the last 6 months. The exclusion criteria will be any contraindication to exercise and
      medical conditions. Subjects with diverse ethnic backgrounds will be recruited from the
      Tallahassee metropolitan area by advertisement and direct communication.

      Study design:

      After completion of initial screening, cardiovascular function of eligible subjects will be
      evaluated at a room temperature of 4oor 23oC in random order. After baseline measurements,
      subjects will be randomly assigned to Placebo (Malt dextrin) or L-citrulline group for 14
      days. Cardiovascular function will be evaluated at the end of the study.
    

Intervention name(s): L-citrulline
Intervention type(s): Dietary Supplement
Intervention description(s): 2 weeks of L-citrulline supplementation (100mg/kg of body weight).
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: wave reflection; augmentation Index; heart rate variability; wasted left ventricular energy