L-Citrulline and Endothelial Function

Effect of Oral L-Citrulline on the Peripheral and Central Endothelial Function in Young and Older Adults

The effect of L-Citrulline is well studied in relation to muscle strength, exhaustion, exercise performance, and endothelial function in health and disease. This study will extend current body of knowledge and will investigate the effect of L-Citrulline on brain vascular function.

Study Overview

• Status: Completed
• Conditions: Aging
• Intervention / Treatment: Drug: L-Citrulline, capsule

Detailed Description

Endothelial function is associated with nitric oxide (NO) availability for vasodilation, blood pressure and blood flow regulation, and vascular health. A large body of evidence demonstrates that aging is associated with a decrease in bioavailability of NO, with more pronounced decrease in sedentary individuals. NO can be produced via the NO synthase (NOS) enzymes, which catalyze the conversion of L-Arginine - a semi-essential amino acid found in fish, nuts and legumes amongst others - to L-Citrulline and produce NO as an endproduct. While the effect of L-Citrulline is extensively studied in relation to muscle strength, exhaustion, exercise performance, as well as on endothelial function in healthy and diseased individuals (including obese and those with heart failure), the effect of L-Citrulline on brain vascular function is not well studied.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73117
      • Andriy Yabluchanskiy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 21-45 and ≥55-90 years of age
• Adequate hearing and visual acuity to participate in the examinations
• Ability to read and write in English
• Competence to provide informed consent

Exclusion Criteria:

• Active CNS disease including multiple sclerosis, uncontrolled seizures, active brain cancer
• Cerebrovascular accident other than TIA within 60 days prior to Visit 0
• Major psychiatric disease, including major depression not currently controlled on medications, alcohol or drug abuse
• Treatment with other Citrulline enhancers (L-Arginine, L-Citrulline Malate) within 4 weeks prior to Visit 0
• Any other medical condition which, in the opinion of investigator, would render the patient inappropriate or too unstable to complete the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-Citrulline; L-Citrulline 50 g/day per os for 1 week	Drug: L-Citrulline, capsule; 5g/daily dose for the duration of 1 week intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in neurovascular coupling using functional near infrared spectroscopy (fNIRS)	Functional near infrared spectroscopy (fNIRS) will be performed during the cognitive n-back task. fNIRS approach generates data that represent a relative change in oxygenated and deoxygenated hemoglobin measured over the cortical brain tissues. Neurovascular coupling will be evaluated as a change in oxy- and deoxy-hemoglobin between before and after treatment. Units of measure - beta. Reported as a %change from baseline, before and after treatment.	1 week
Change in neurovascular coupling using the dynamic retinal vessel analysis	Flicker light-induced dilation of the retinal vessels (percentage increase over baseline diameter) will be measured in the right or left eye of each study participant using the Dynamic Vessel Analyzer (DVA, IMEDOS Systems, Jena, Germany). Units of measure mm, reported as a %change from baseline, before and after treatment.	1 week
Change in neuronal activity	EEG signal will be collected to generate spectral data. These data will be used for comparison of EEG activity between before and after treatment. Units of measure - power spectral density. Reported as a %change from baseline, before and after treatment.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in microvascular endothelial function	Changes in microvascular endothelial function will be assessed using laser speckle contrast imaging (LSCI) in the hand using the flow mediated dilation approach. The change in skin perfusion is calculated and reported as a %change from baseline, between before and after treatment. Units of measure - perfusion index (arbitrary units). Reported as a %change from baseline, before and after treatment.	1 week
Change in macrovascular endothelial function	Changes in macrovascular endothelial function will be assessed using sonography during flow mediated dilation approach. The change in brachial artery diameter (mm) is calculated and reported as a %change from baseline, between before and after treatment.	1 week
Change in Glycocalyx - perfused boundary region	Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include perfused boundary region (um), and will be used for comparison before and after treatment.	1 week
Change in capillary density	Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include capillary density (mm/mm^2), and will be used for comparison before and after treatment.	1 week
Change in red blood cell velocity	Video recordings of the sublingual vasculature will be performed using the high definition video camera GlycoCheck (Microvascular health solutions). Data collected will include red blood cell velocity (um/sec), and will be used for comparison before and after treatment.	1 week
Change in grip strength	The change in hand grip strength will be measured before and after intervention. Data collected will include measurements of power in kg for left and right hand respectively	1 week
Change in Attention	CANTAB research attention test.Reported as a %change from baseline, before and after treatment.	1 week
Change in Working Memory	CANTAB research working memory test.Reported as a %change from baseline, before and after treatment.	1 week
Change in Executive Function	CANTAB research executive function test.Reported as a %change from baseline, before and after treatment.	1 week
Change in Processing Speed	CANTAB research processing speed test.Reported as a %change from baseline, before and after treatment.	1 week
Blood collection	Blood samples will be collected to measure L-Citrullin related metabolites.	1 week

Collaborators and Investigators

• Sponsor: University of Oklahoma
• Investigators: Principal Investigator: Andriy Yabluchanskiy, MD, PhD, University of Oklahoma

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2024
• Primary Completion (Actual): November 28, 2024
• Study Completion (Actual): December 28, 2024

Study Registration Dates

• First Submitted: February 1, 2023
• First Submitted That Met QC Criteria: February 1, 2023
• First Posted (Actual): February 10, 2023

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: L-Citrulline
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Pharmaceutical Preparations; Dosage Forms; Amino Acids; Amino Acids, Diamino; Capsules; Citrulline
• Other Study ID Numbers: 15485

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: PhysioNet

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No