L-citrulline Supplementation, Cold Exposure, & Post-Exercise Muscle Ischemia
Condition: Hypertension
MeSH terms: Ischemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Cardiovascular disease (CVD) continues to be the major cause of morbidity and mortality in
      western countries. It has been shown that CVD events are known to be higher in the winter
      than in the summer. Low environmental temperatures may induce increased cardiovascular stress
      resulting in cold-induced hypertension (CIH), the leading risk factor for CVD events. Similar
      to whole-body cold exposure, the cold pressor test (CPT), an external local cold stimulus,
      has been used for evaluation of cardiovascular and hemodynamic reactivity to sympathetic
      stimulation. It has been shown that brachial blood pressure (BP), pressure pulse wave
      reflection, aortic BP, heart rate (HR), and arterial stiffness are increased during CPT.
      However, the physiologic mechanisms for the cardiovascular complications related to low
      temperatures are not completely clear.

      Isometric-handgrip (IHG) exercise has been used as a tool for assessing cardiovascular
      autonomic control by a maneuver defined as post-exercise muscle ischemia (PEMI). PEMI induces
      exercise pressor reflex (metaboreflex) by trapping metabolites in the previous active muscle
      at the cessation of exercise. During PEMI, the accumulation of contraction-derived
      metabolites induces sympathetic mediated vascular stimulation and an increased BP, whereas
      the HR fully recovers. This suggests that the fall in HR is evoked by an increase in
      parasympathetic activity which overpowers the sympathetic activation. Implication of IHG
      exercise followed by PEMI provides important clinical information because impaired autonomic
      and cardiovascular functions are associated with cardiovascular events.

      Recently, oral supplementation with the amino acid L-citrulline (L-cit) has been proposed as
      a possible adjunct treatment for hypertension and arterial stiffness. L-cit is known to
      enhance the bioavailability of L-arginine (L-arg), the endothelial substrate for nitric oxide
      (NO) production. Cold exposure might include a temperature-dependent inhibition of
      endothelial NO synthase (eNOS), the enzyme that produces NO from the amino acid L-arg and may
      trigger various types of CVD. It has been shown that L-cit supplementation has effectively
      attenuated the CIH response during cold pressor test. Thus, L-cit supplementation may be
      effective to reduce the cardiovascular responses associated with cold exposure and the
      exercise pressor reflex imposed by PEMI. Therefore, the proposed study is important for the
      following reasons: (1) the results of his study will add to our understanding regarding the
      cardiovascular and autonomic mechanisms associated with exercise and cold exposure; (2) the
      results of this study will contribute to the development of an adjunct therapy for the
      prevention of cardiovascular adverse events that are particularly increased during stress
      such as cold exposure and exercise.
    

Detailed description: 
      Specific Aims

      AIM 1: To determine the acute effects of the exercise pressor response imposed by PEMI with
      and without CPT on hemodynamics and cardiac autonomic regulation in health overweight/obese
      men.

      AIM 2: To examine the effects of a 14-day course of L-cit supplementation on arterial
      stiffness, aortic hemodynamics, and autonomic regulation at rest and during conditions
      characterized by increased sympathetic activity (IHG, PEMI, and PEMI concurrent with CPT).

      Research Hypotheses

      Hypothesis 1: There will be greater increases in peripheral and central BP, arterial
      stiffness, wave reflection, and cardiac sympathetic activity during PEMI concurrent with CPT
      than during PEMI alone.

      Hypothesis 2: 14 days of L-cit supplementation will attenuate peripheral and central BP, wave
      reflection, arterial stiffness, and cardiac sympathetic activity responses during IHG
      exercise, PEMI, and PEMI concurrent with CPT compared with placebo (PL) supplementation.

      Description of the study

      A total of twenty male young adults (18-35 years) with overweight or obesity [body mass index
      (BMI) >25 and <40 kg/m2] will be enrolled in this study. All of the subjects will be
      nonsmokers, no L-cit or L-arg users or regular exercisers (defined as more than 120 min per
      week) at least 6 months before the study begins. Subjects will be asked to maintain their
      diet and exercise habits during the study period.

      Study design:

      After completion of initial screening, cardiovascular and autonomic function of eligible
      subjects will be evaluated in a quiet temperature-controlled room (22-24°C). After baseline
      measurement, in a cross-over design fashion, subjects will be randomized to either Placebo
      group (Maltodextrin) or L-citrulline group for the first 14 days of the study that will be
      followed by a 14 day washout period and then will be crossed over to their next treatment.
      Cardiovascular function will be evaluated at baseline and after 14 days of the first and the
      second treatment. Measurements will be conducted in the morning after at least 8 hours of an
      overnight fast in order to avoid potential diurnal variations in BP and vascular reactivity.
    

Intervention name(s): L-citrulline
Intervention type(s): Dietary Supplement
Intervention description(s): 2 weeks of L-citrulline supplementation (6g/day).
Other intervention name(s): 2 weeks of L-citrulline supplementation (6g/day).
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: wave reflection; augmentation Index; heart rate variability; arterial stiffness