l-Citrulline Supplementation: Impact on Cardiometabolic Health

Nutrients. 2018 Jul 19;10(7):921. doi: 10.3390/nu10070921.

Abstract

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Keywords: adipocytes; aging; arginine; cardiovascular disease; diabetes; endothelial function; enterocytes; flow mediated dilation; hypertension; immune cells; inflammation; insulin resistance; interventions; liver; mitochondria; muscle; nitric oxide; obesity; supplements; therapeutics; watermelon.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / metabolism
  • Antihypertensive Agents / therapeutic use*
  • Antioxidants / adverse effects
  • Antioxidants / metabolism
  • Antioxidants / therapeutic use
  • Citrulline / adverse effects
  • Citrulline / metabolism
  • Citrulline / therapeutic use*
  • Diabetic Angiopathies / immunology
  • Diabetic Angiopathies / metabolism
  • Diabetic Angiopathies / physiopathology
  • Diabetic Angiopathies / prevention & control*
  • Dietary Supplements* / adverse effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology
  • Evidence-Based Medicine*
  • Humans
  • Hypertension / immunology
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance
  • Metabolic Syndrome / immunology
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / physiopathology
  • Metabolic Syndrome / therapy
  • Models, Biological*
  • Sarcopenia / immunology
  • Sarcopenia / metabolism
  • Sarcopenia / physiopathology
  • Sarcopenia / prevention & control
  • Vascular Stiffness
  • Vasodilator Agents / adverse effects
  • Vasodilator Agents / metabolism
  • Vasodilator Agents / therapeutic use

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antihypertensive Agents
  • Antioxidants
  • Hypoglycemic Agents
  • Vasodilator Agents
  • Citrulline