2 Weeks of Citrulline Supplementation on Arterial Function in Postmenopausal Women With Elevated Blood Pressure or Hypertension

Study Overview
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Brief Summary
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The objective of this project is to elucidate the effect of L-Citrulline (L-CIT) supplementation on vascular function at rest and during rhythmic handgrip exercise and functional sympatholysis via lower-body negative pressure in postmenopausal women with elevated blood pressure and hypertension.

Detailed Description
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Using a double-blind, randomized, placebo-controlled, and crossover design, overweight or obese postmenopausal women with elevated blood pressure (BP) or hypertension will receive CIT (6 grams/day) or placebo for 2 weeks, separated by a two-week washout period. There will be a total of 5 laboratory visits. The 1st visit will take approximately 1 hour. The 2nd - 5th visits will take about 2 hours and 15 minutes. Visit 1 will be a screening visit, visits 2 and 4 will be considered baseline visits, and visits 3 and 5 will be following the participants' two weeks of supplementation. Arterial stiffness (carotid-femoral and femoral-dorsalis pedis pulse wave velocity) and endothelial function will be assessed at rest. Additionally, brachial artery blood flow, forearm muscle oxygenation, cardiovascular hemodynamics (stroke volume, cardiac output, systemic vascular resistance), and BP will be assessed at rest, during 6 minutes of rhythmic handgrip exercise at 30% of a predetermined maximal voluntary contraction, and 2 minutes of superimposed lower body negative pressure to increase sympathetic activity.

Official Title
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2 Weeks of L-Citrulline Supplementation Improves Arterial Function and Systolic Blood Pressure at Rest and During Exercise in Postmenopausal Women With Elevated Blood Pressure and Hypertension

Conditions
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Menopause, Hypertension

Intervention / Treatment
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* Dietary Supplement: L-Citrulline
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (defined as the absence of menstruation for at least 1 year). Resting systolic blood pressure 120-150 mmHg. Between the ages of 50 - 70 years. Sedentary (< 120 minutes of exercise/week). Body mass index of 25 - 39.9 kg/m2. Fasting glucose < 126 mg/dL and HbA1c < 6.5%. Exclusion Criteria: Body mass index ≥ 40 or < 25 kg/m2. Systolic blood pressure > 150 mmHg. Taking more than two antihypertensive medications. Cardiovascular diseases, type I/II diabetes, musculoskeletal disorders, or cancer. Changes in hypertensive medication in the past three months. Began or changed hormone replacement therapy in the past 6 months. Current smoker. Heavy drinking (> 7 alcoholic drinks/week). Participants on beta-blockers or other vasodilatory supplements (nitrates). Incorporated in a weight loss program and/or aerobic or resistance training program.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Cross-Over Assignment Double (Participant, Investigator) randomized, double-blind, placebo-controlled, cross-over study design
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-Citrulline<br>L-Citrulline: 6 grams/day divided in 2 equal doses | Dietary Supplement: L-Citrulline<br>* 2 weeks of L-Citrulline supplementation (6 grams/day)<br>|
| Placebo Comparator: Placebo<br>Microcrystalline cellulose: 8 capsules/day divided into 2 equal doses | Dietary Supplement: Placebo<br>* 2 weeks of microcrystalline cellulose supplementation (8 capsules/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrovascular endothelial function at rest | Endothelial function will be assessed via brachial artery flow-mediated vasodilation (ultrasonography) during reactive hyperemia at baseline and after 2 weeks of each supplementation. | 2 weeks of each intervention | 
| Microvascular endothelial function at rest | Endothelial function will be assessed via peripheral arterial tonometry (endoPAT) during reactive hyperemia at baseline and after 2 weeks of each supplementation. | 2 weeks of each intervention | 
| Microvascular endothelial function at rest | Endothelial function will be assessed using forearm muscle oxygen saturation (near-infrared spectroscopy) during reactive hyperemia before and after 2 weeks of each supplementation. | 2 weeks of each intervention | 
| Brachial artery blood flow at rest and during rhythmic handgrip exercise with and without lower-body negative pressure | Blood flow will be measured via Doppler ultrasound before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Forearm muscle oxygenation at rest and during rhythmic handgrip exercise with and without lower-body negative pressure | Muscle oxygen saturation will be measured via near-infrared spectroscopy before and after 2 weeks of each intervention. | 2 weeks of each intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beat-to-beat blood pressure at rest and during rhythmic handgrip exercise with and without lower-body negative pressure | Blood pressure will be measured via a finger cuff (finometer) before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Aortic hemodynamics at rest and during rhythmic handgrip exercise with and without lower body negative pressure | Aortic blood pressure and pressure waves will be assessed using radial applanation tonometry before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Stroke volume at rest and during rhythmic handgrip exercise with and without lower body negative pressure | Stroke volume will be assessed via impedance cardiography before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Heart rate at rest and during rhythmic handgrip exercise with and without lower body negative pressure | Heart rate will be assessed via impedance cardiography before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Systemic vascular resistance at rest and during rhythmic handgrip exercise with and without lower body negative pressure | Systemic vascular resistance will be assessed via impedance cardiography before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Central and peripheral arterial stiffness at rest | Carotid-femoral and femoral-dorsalis pedis pulse wave velocity will be measured using arterial applanation tonometry before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Forearm muscle strength | Maximal forearm muscle strength will be measured using a handgrip dynamometer before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| L-arginine levels | Serum levels of l-arginine will be assessed before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| Nitric oxide levels | Serum levels of nitric oxide will be assessed before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| L-citrulline levels | Serum levels of l-citrulline will be assessed before and after 2 weeks of each intervention. | 2 weeks of each intervention | 
| L-ornithine levels | Serum levels of l-ornithine will be assessed before and after 2 weeks of each intervention. | 2 weeks of each intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endothelial function, Blood flow, Blood pressure, Functional sympatholysis