Effect of Oral Caffeine and L-Citrulline Supplementation on Arterial Function in Healthy Males

• ClinicalTrials.gov Identifier: NCT02214290
• Recruitment Status: Completed
• First Posted: August 12, 2014
• Results First Posted: December 29, 2020
• Last Update Posted: December 29, 2020
• Sponsor: Florida State University
• Information provided by (Responsible Party): Arturo Figueroa, Florida State University

Study Description

Brief Summary:

Caffeine is an exceedingly popular and consumed pharmacological agent. Although caffeine is primarily consumed from coffee and tea beverages, it is also available in other forms such as sodas, energy drinks, tablets and capsules. Nevertheless, caffeine acutely increases brachial and aortic systolic blood pressure (BP) and arterial stiffness. Arterial stiffness is an independent predictor of cardiovascular disease (CVD) and assessed through pulse wave velocity (PWV). Interestingly, previous studies have proposed that caffeine may increase aortic BP through increases in aortic PWV and augmentation index (AIx), a measurement of wave reflection. Yet, these effects were seen in middle-aged adults with treated hypertension and a wide age range. Therefore, it is imperative to consider that caffeine may cause different effects in young normotensive individuals than in older adults independently of BP levels. Importantly, oral supplementation of the amino-acid, L-citrulline has been shown to enhance the bioavailability of L-arginine levels and nitric oxide (NO) production and, therefore, improve arterial function. L-citrulline supplementation for 7 days given at 6 g/day has shown to increase NO levels while improving PWV. Previous studies by our group also demonstrated that L-citrulline supplementation reduces the BP response to cold exposure; a condition with an increased vasoconstriction. Therefore, the acute effects of caffeine on central and peripheral PWV and BP in healthy young men are yet to be fully evaluated. We hypothesized that acute caffeine intake would increase peripheral and aortic BP and PWV and that L-citrulline supplementation would attenuate the effects induced by acute caffeine ingestion.

Condition or disease	Intervention/treatment	Phase
Hypertension; Healthy	Drug: Caffeine; Drug: Placebo; Dietary Supplement: L-citrulline	Not Applicable

Detailed Description:

The specific aims of this study are:

AIM 1: To examine the effects of the acute ingestion of 200mg caffeine (tablets) on arterial function in young adults. The working hypothesis is that acute caffeine intake would increase brachial, ankle and aortic BP, PWV (aortic and leg), and wave reflection. In order to test this hypothesis, the investigators will perform non-invasive measurements of arterial stiffness (aortic and leg PWV) and pulse wave analysis (aortic BP and AIx) using applanation tonometry of the radial artery 30, 45, and 60 minutes following caffeine ingestion.

AIM 2: To determine the effectiveness of L-citrulline supplementation to attenuate the acute cardiovascular effects of caffeine ingestion. The working hypothesis is that 7 days of L-citrulline supplementation will attenuate the unfavorable arterial responses (increases in BP, PWV, and wave reflection) to acute caffeine ingestion. In order to test this hypothesis, the investigators will perform the same procedures previously specified in AIM 1.

Description of the study:

Sixteen healthy young men 18-40 years of age will be enrolled in this study. Participants with CVD history, resting BP (> 160/100 mmHg), recent history of smoking, or considered competitive athlete will be excluded from the study. All subjects will refrain from food and caffeine for > 8 hours and from exercise for > 24 hours before testing.

Study design:

Following an initial screening, arterial function measurements will be collected. Measurements will be assessed at baseline following 10 minutes of rest in the supine position and then again at 30, 45, and 60 minutes after 200 mg caffeine or placebo ingestion. Participants will receive caffeine or placebo supplementation on two separate visits with a minimum of 48 hours in between sessions. Following the acute phase of the study, subjects will be randomized to consume L-citrulline or placebo for 7 days given at 6 grams/day. Following the same protocol as the acute phase with 200 mg caffeine, measurements will be collected before and after the 7 day supplementation period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Effect of Oral Caffeine and L-Citrulline Supplementation on Arterial Function in Healthy Males
• Study Start Date: September 2012
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: March 2014

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Caffeine; 200 mg caffeine tablet produced by CVS Pharmacy, USA	Drug: Caffeine; A 200 mg caffeine tablet was given to subject to examine the drugs effect on arterial function.; Other Name: Caffeine tablet (CVS Pharmacy)
Placebo Comparator: Placebo; Placebo pill produced by NOW FOODS, USA	Drug: Placebo; A 750 mg placebo capsule (maltodextrin) was given to subjects to examine the effect of the drug on arterial function.; Other Name: Placebo from NOW FOODS, USA
Experimental: L-citrulline; L-citrulline capsule (750 mg) provided by NOW FOODS	Dietary Supplement: L-citrulline; L-citrulline was used to examine the effect of the supplement on arterial function.; Other Name: L-citrulline (750 mg/capsule)

Outcome Measures

Primary Outcome Measures :

1. Aortic Blood Pressure [ Time Frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points) ]
   Aortic blood pressure at rest and 30 minutes after acute ingestion of 200 mg of caffeine before and after 7 days of either 6g/day of Citrulline or 6 g/day of Placebo.

Secondary Outcome Measures :

1. Changes in Reflected Wave Pressure (P2) [ Time Frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points) ]
   Reflected wave pressure at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.
2. Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day) [ Time Frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points) ]
   Femoral-ankle pulse wave velocity at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Young healthy males
• Non smoker
• Non endurance trained athlete
• No previous history of cardiovascular disease

Exclusion Criteria:

• Female
• Blood pressure greater than 160/100
• Smoker

Contacts and Locations

Sponsors and Collaborators

Florida State University

Investigators

• Principal Investigator: Arturo Figueroa, M.D. Ph.D; Florida State University

More Information

• Responsible Party: Arturo Figueroa, Associate Professor, Florida State University
• ClinicalTrials.gov Identifier: NCT02214290
• Other Study ID Numbers: HSC2013.10514
• First Posted: August 12, 2014
• Results First Posted: December 29, 2020
• Last Update Posted: December 29, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Arturo Figueroa, Florida State University:

Cardiovascular; Caffeine; L-citrulline; Arterial Function; Hemodynamics; Blood Pressure; Pulse Wave Velocity; Pulse Wave Analysis

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Caffeine; Central Nervous System Stimulants; Physiological Effects of Drugs; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Purinergic P1 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents