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

• Sponsor: Florida State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02214290
• Collaborator: (none)
• Enrollment: 16
• Arms: 3
• Duration (Months): 17.9

Study Details

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	N/A

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
• 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: Sep 1, 2012
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 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 Names: 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 Names: 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 Names: L-citrulline (750 mg/capsule)

Outcome Measures

Primary Outcome Measures

1. Aortic Blood Pressure [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) [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) [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

Criteria

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

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

Locations

No locations specified.

Sponsors and Collaborators

• Florida State University

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arturo Figueroa, Associate Professor, Florida State University
• ClinicalTrials.gov Identifier: NCT02214290
• Other Study ID Numbers: HSC2013.10514
• First Posted: Aug 12, 2014
• Last Update Posted: Dec 29, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Arturo Figueroa, Associate Professor, Florida State University: Cardiovascular; Caffeine; L-citrulline; Arterial Function; Hemodynamics; Blood Pressure; Pulse Wave Velocity; Pulse Wave Analysis
• Additional relevant MeSH terms: Hypertension; Caffeine

Study Results

Participant Flow

Recruitment Details	Sixteen young healthy men participated in this study. All subjects were non-smokers, recreationally active, and free of apparent cardiovascular-metabolic diseases based on medical history.
Pre-assignment Detail	Of the 42 individuals screened, 16 individuals completed the intervention in its entirety.

Arm/Group Title	Citrulline First, Then Placebo	Placebo First, Then L-Citrulline
Arm/Group Description	Each participant received L-Citrulline (6g/day) for a 7 day period. This was followed by a 14 day washout period. Finally, the same participants then received a Placebo (6g/day maltodextrin) for a 7 day period.	Each participant received a Placebo (6g/day maltodextrin) for a 7 day period. This was followed by a 14 day washout period. Finally, the same participants then received a L-Citrulline (6g/day) for a 7 day period.
Period Title: First Intervention (7 Days)
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention (7 Days)
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention (7 Days)
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	L-Citrulline or Placebo
Arm/Group Description	Placebo and L-Citrulline pills produced by NOW FOODS, USA Citrulline or Placebo (both 6g/day) were given for a 7 day supplementation period. This was followed by a 14 day washout period and crossover to the other supplement (L-Citrulline or Placebo) for 7 days. Measurements of arterial function were performed to determine if the supplements had any significant effect on blood pressure control/pressure wave reflection at rest and immediately after ingestion of 200 milligrams of caffeine.
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23 (3)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	16 100%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	16 100%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Aortic Blood Pressure
Description	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.
Time Frame	Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)

Outcome Measure Data

Analysis Population Description

Young, apparently healthy individuals, aged 18-40 years old.

Arm/Group Title	Citrulline	Placebo
Arm/Group Description	Participants received 6g/day of Citrulline for 7 days	Participants received 6 g/day of Maltodextrin for 7 days.
Measure Participants	16	16
Baseline	5 (1)	6 (1)
7 Days	4 (1)	4 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citrulline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments	post-hoc comparisons were used to determine within-group and between-group differences.

2. Secondary Outcome

Title	Changes in Reflected Wave Pressure (P2)
Description	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.
Time Frame	Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)

Outcome Measure Data

Analysis Population Description

Young, apparently healthy adults, aged 18-40 years.

Arm/Group Title	Citrulline	Placebo
Arm/Group Description	Participants received 6g/day of Citrulline for 7 days	Participants received 6 g/day of Placebo
Measure Participants	16	16
Baseline	5 (1)	5 (1)
7 Days	4 (1)	5 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citrulline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments	post-hoc comparisons were used to determine within-group and between-group differences.

3. Secondary Outcome

Title	Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day)
Description	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.
Time Frame	Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)

Outcome Measure Data

Analysis Population Description

young, apparently healthy adults, aged 18-40 years

Arm/Group Title	Citrulline	Placebo
Arm/Group Description	Participants received a 6 g/day of Citrulline for 7 days	Participants received a 200 mg maltodextrin tablet, and femoral-ankle pulse wave velocity was taken at 60 minutes post-ingestion.
Measure Participants	16	16
Baseline	0.6 (0.4)	0.7 (0.5)
7 Days	0.4 (0.4)	0.6 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citrulline, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments	post-hoc comparisons were used to determine within-group and between-group differences.

Adverse Events

Adverse Event Reporting Description	Adverse events were not monitored/assessed because the participants were young and healthy.
Arm/Group Title	Citrulline		Placebo
Arm/Group Description	Participants received 6g/day of Citrulline for 7 days		Participants received 6g/day of Placebo (Maltodextrin) for 7 days
All Cause Mortality
	Citrulline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Citrulline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Citrulline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.