Cheese Consumption and Human Microvascular Function

Study Overview
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Brief Summary
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Increased dairy intake is associated with improved measures of blood vessel health. Dairy cheese, however, is often high in sodium. Dietary sodium can impair blood vessel function. The researchers examine if and how natural cheese may protect against impairments in blood vessel function caused by sodium. For this study, participants complete four 8-day controlled feeding periods in which they eat cheese (6 oz/day) or no cheese during a low-sodium or high-sodium base-diet. The participants complete baseline experiments while on their normal personal diet and then repeat experiments at the end of each controlled feeding period. In some of our experiments, the researchers use a technique called microdialysis (MD). With MD, the researchers perfuse some research drugs into the skin on the forearm through tiny tubing that mimics capillaries. These MD drugs mimic or block substances the body naturally makes to control the small blood vessels in the skin. The drugs remain in nickel-sized areas around the tubing and do not go into the rest of the body. The researchers also use a standard technique called flow mediated dilation (FMD) that uses blood pressure cuffs and ultrasound to look at the health of larger blood vessels in the body. FMD includes placing a small tablet of nitroglycerin under the tongue during part of the test.

Detailed Description
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Subject screening will be performed by the Penn State Clinical Translational Research Center (CTRC) medical staff and will include a physical exam by a clinician, anthropometry, and a chemical and lipid profile, liver and renal function. Participants meet with a registered dietitian to determine their caloric energy requirements and identify food preferences. The interview includes surveying the subject's physical activity over the previous 7 days. Subjects will undergo baseline microdialysis experiments to examine the function of the blood vessels in the skin microcirculation. Subjects will also go through a baseline assessment of conduit vessel endothelial and vascular smooth muscle function with brachial artery flow-mediated vasodilation (FMD), and sublingual nitroglycerin. Following baseline experiments, subjects participate in 4 controlled feeding periods, each 8 days in duration. The controlled feeding periods are assigned in a randomized order. At the end of each 8-day controlled dietary period, subjects will repeat microdialysis experiments, brachial artery FMD, and responsiveness to sublingual nitroglycerin.

Official Title
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Cheese Consumption and Human Microvascular Function

Conditions
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Microvascular Dysfunction

Intervention / Treatment
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* Drug: Acetylcholine (ACh) Dose Response
* Drug: Local Heating (LH)
* Drug: Flow Mediated Dilation with nitroglycerin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Seated systolic pressure 120-140 mmHg Seated diastolic pressure 70-90 mmHg. Normoglycemic (HbA1C <5.7%) Exclusion Criteria: Taking pharmacotherapy that alters peripheral vascular control Pregnancy Breastfeeding Females taking contraceptives (pills, patches, shots, etc.) or hormone replacement therapy Taking illicit and/or recreational drugs Use of nicotine containing-products (e.g. smoking, chewing tobacco, etc.) Known allergy to latex or investigative substances

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: All subjects participate in 4 diets in randomized order. The diets differ in the amount of sodium and dairy cheese content. Each diet is consumed for 8 days. Minimum washout of 1 week between diets. Baseline experiment is conducted prior to first dietary intervention, and the experiment is repeated after each dietary intervention.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Baseline<br>Subjects on normal personal diet Acetylcholine (ACh) Dose Response, Local heating (LH), and Flow Mediated Dilation with nitroglycerin experiments | Drug: Acetylcholine (ACh) Dose Response<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + N-G-nitro-L-arginine methyl ester (LNAME) Probe 3. Lactated Ringer's + Ascorbate Probe 4. Lactated Ringer's + Tempol Probe 5. Lactated Ringer's + Apocynin<br>* Other names: ACh Dose Response;Drug: Local Heating (LH)<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + Ascorbate Probe 3. Lactated Ringer's + Tempol Probe 4. Lactated Ringer's + Apocynin<br>* Other names: LH;Drug: Flow Mediated Dilation with nitroglycerin<br>* BP cuff on a forearm, gel on the upper arm just above the elbow, and a Doppler ultrasound probe on the gel. The ultrasound measures vessel size and blood velocity. After a 3-minute resting measurement, the cuff inflates for 5 minutes to occlude forearm blood flow (BF). After the cuff deflates, we perform a second reading. Sublingual nitroglycerin: The subject is supine. We measure blood pressure. Also, we perform ultrasonography at the brachial artery at the elbow during the procedure. Nurse places a 0.4 mg nitroglycerin tablet under the subject's tongue. The subject remains supine for 20 minutes following the nitroglycerin administration.<br>* Other names: FMD;|
| Experimental: Low Sodium, No Cheese<br>Diet contains 1,500 mg sodium per day Diet does not contain dairy cheese After 8 days on diet: Acetylcholine Dose Response, Local heating, and Flow Mediated Dilation with nitroglycerin experiments | Drug: Acetylcholine (ACh) Dose Response<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + N-G-nitro-L-arginine methyl ester (LNAME) Probe 3. Lactated Ringer's + Ascorbate Probe 4. Lactated Ringer's + Tempol Probe 5. Lactated Ringer's + Apocynin<br>* Other names: ACh Dose Response;Drug: Local Heating (LH)<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + Ascorbate Probe 3. Lactated Ringer's + Tempol Probe 4. Lactated Ringer's + Apocynin<br>* Other names: LH;Drug: Flow Mediated Dilation with nitroglycerin<br>* BP cuff on a forearm, gel on the upper arm just above the elbow, and a Doppler ultrasound probe on the gel. The ultrasound measures vessel size and blood velocity. After a 3-minute resting measurement, the cuff inflates for 5 minutes to occlude forearm blood flow (BF). After the cuff deflates, we perform a second reading. Sublingual nitroglycerin: The subject is supine. We measure blood pressure. Also, we perform ultrasonography at the brachial artery at the elbow during the procedure. Nurse places a 0.4 mg nitroglycerin tablet under the subject's tongue. The subject remains supine for 20 minutes following the nitroglycerin administration.<br>* Other names: FMD;|
| Experimental: Low Sodium, Cheese<br>Diet contains 1,500 mg sodium per day Diet contains 6 oz dairy cheese per day After 8 days on diet: Acetylcholine Dose Response, Local heating, and Flow Mediated Dilation with nitroglycerin experiments | Drug: Acetylcholine (ACh) Dose Response<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + N-G-nitro-L-arginine methyl ester (LNAME) Probe 3. Lactated Ringer's + Ascorbate Probe 4. Lactated Ringer's + Tempol Probe 5. Lactated Ringer's + Apocynin<br>* Other names: ACh Dose Response;Drug: Local Heating (LH)<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + Ascorbate Probe 3. Lactated Ringer's + Tempol Probe 4. Lactated Ringer's + Apocynin<br>* Other names: LH;Drug: Flow Mediated Dilation with nitroglycerin<br>* BP cuff on a forearm, gel on the upper arm just above the elbow, and a Doppler ultrasound probe on the gel. The ultrasound measures vessel size and blood velocity. After a 3-minute resting measurement, the cuff inflates for 5 minutes to occlude forearm blood flow (BF). After the cuff deflates, we perform a second reading. Sublingual nitroglycerin: The subject is supine. We measure blood pressure. Also, we perform ultrasonography at the brachial artery at the elbow during the procedure. Nurse places a 0.4 mg nitroglycerin tablet under the subject's tongue. The subject remains supine for 20 minutes following the nitroglycerin administration.<br>* Other names: FMD;|
| Experimental: High Sodium, No Cheese<br>Diet contains 5,500 mg sodium per day Diet does not contain dairy cheese After 8 days on diet: Acetylcholine Dose Response, Local heating, and Flow Mediated Dilation with nitroglycerin experiments | Drug: Acetylcholine (ACh) Dose Response<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + N-G-nitro-L-arginine methyl ester (LNAME) Probe 3. Lactated Ringer's + Ascorbate Probe 4. Lactated Ringer's + Tempol Probe 5. Lactated Ringer's + Apocynin<br>* Other names: ACh Dose Response;Drug: Local Heating (LH)<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + Ascorbate Probe 3. Lactated Ringer's + Tempol Probe 4. Lactated Ringer's + Apocynin<br>* Other names: LH;Drug: Flow Mediated Dilation with nitroglycerin<br>* BP cuff on a forearm, gel on the upper arm just above the elbow, and a Doppler ultrasound probe on the gel. The ultrasound measures vessel size and blood velocity. After a 3-minute resting measurement, the cuff inflates for 5 minutes to occlude forearm blood flow (BF). After the cuff deflates, we perform a second reading. Sublingual nitroglycerin: The subject is supine. We measure blood pressure. Also, we perform ultrasonography at the brachial artery at the elbow during the procedure. Nurse places a 0.4 mg nitroglycerin tablet under the subject's tongue. The subject remains supine for 20 minutes following the nitroglycerin administration.<br>* Other names: FMD;|
| Experimental: High Sodium, Cheese<br>Diet contains 5,500 mg sodium per day Diet contains 6 oz dairy cheese per day After 8 days on diet: Acetylcholine Dose Response, Local heating, and Flow Mediated Dilation with nitroglycerin experiments | Drug: Acetylcholine (ACh) Dose Response<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + N-G-nitro-L-arginine methyl ester (LNAME) Probe 3. Lactated Ringer's + Ascorbate Probe 4. Lactated Ringer's + Tempol Probe 5. Lactated Ringer's + Apocynin<br>* Other names: ACh Dose Response;Drug: Local Heating (LH)<br>* Probe 1. Lactated Ringer's only (control) Probe 2. Lactated Ringer's + Ascorbate Probe 3. Lactated Ringer's + Tempol Probe 4. Lactated Ringer's + Apocynin<br>* Other names: LH;Drug: Flow Mediated Dilation with nitroglycerin<br>* BP cuff on a forearm, gel on the upper arm just above the elbow, and a Doppler ultrasound probe on the gel. The ultrasound measures vessel size and blood velocity. After a 3-minute resting measurement, the cuff inflates for 5 minutes to occlude forearm blood flow (BF). After the cuff deflates, we perform a second reading. Sublingual nitroglycerin: The subject is supine. We measure blood pressure. Also, we perform ultrasonography at the brachial artery at the elbow during the procedure. Nurse places a 0.4 mg nitroglycerin tablet under the subject's tongue. The subject remains supine for 20 minutes following the nitroglycerin administration.<br>* Other names: FMD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| laser Doppler blood flow | This measurement is performed using a laser Doppler flow meter. The flow meter produces a non-invasive qualitative and dimensionless index of blood flow in blood vessels. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic Blood Pressure | Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The peak blood pressure during a cardiac cycle when the heart contracts. | 8 weeks | 
| Diastolic Blood Pressure | Blood pressure is measured via brachial auscultation manually or with a critical care monitor. The lowest blood pressure during a cardiac cycle when the heart is between beats. | 8 weeks | 
| Flow Mediated Dilation | Flow mediated dilation is measured through Doppler ultrasound probe placed at brachial artery. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sodium, Hypertension, Blood Pressure, Cardiovascular Disease, Nitric Oxide, Skin, Dairy, Cheese, Oxidative Stress, Diet, Flow Mediated Vasodilation, Nitroglycerin, Superoxide, Microcirculation