Cheese Consumption and Human Microvascular Function

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.

Study Overview

• Status: Completed
• Conditions: Microvascular Dysfunction
• Intervention / Treatment: Drug: Acetylcholine (ACh) Dose Response; Drug: Local Heating (LH); Drug: Flow Mediated Dilation with nitroglycerin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • University Park, Pennsylvania, United States, 16802
      • Pennsylvania State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Baseline; Subjects on normal personal diet Acetylcholine (ACh) Dose Response, Local heating (LH), and Flow Mediated Dilation with nitroglycerin experiments	Drug: Acetylcholine (ACh) Dose Response; 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; Other Names: ACh Dose Response; Drug: Local Heating (LH); 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; Other Names: LH; Drug: Flow Mediated Dilation with nitroglycerin; 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.; Other Names: FMD
EXPERIMENTAL: Low Sodium, No Cheese; 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; 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; Other Names: ACh Dose Response; Drug: Local Heating (LH); 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; Other Names: LH; Drug: Flow Mediated Dilation with nitroglycerin; 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.; Other Names: FMD
EXPERIMENTAL: Low Sodium, Cheese; 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; 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; Other Names: ACh Dose Response; Drug: Local Heating (LH); 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; Other Names: LH; Drug: Flow Mediated Dilation with nitroglycerin; 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.; Other Names: FMD
EXPERIMENTAL: High Sodium, No Cheese; 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; 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; Other Names: ACh Dose Response; Drug: Local Heating (LH); 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; Other Names: LH; Drug: Flow Mediated Dilation with nitroglycerin; 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.; Other Names: FMD
EXPERIMENTAL: High Sodium, Cheese; 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; 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; Other Names: ACh Dose Response; Drug: Local Heating (LH); 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; Other Names: LH; Drug: Flow Mediated Dilation with nitroglycerin; 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.; Other Names: FMD

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Lacy M. Alexander
• Collaborators: National Dairy Council

Publications and helpful links

General Publications

• Alba BK, Stanhewicz AE, Dey P, Bruno RS, Kenney WL, Alexander LM. Controlled Feeding of an 8-d, High-Dairy Cheese Diet Prevents Sodium-Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy, Older Adults through Reductions in Superoxide. J Nutr. 2020 Jan 1;150(1):55-63. doi: 10.1093/jn/nxz205.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2016
• Primary Completion (ACTUAL): March 1, 2021
• Study Completion (ACTUAL): March 1, 2021

Study Registration Dates

• First Submitted: December 13, 2017
• First Submitted That Met QC Criteria: December 13, 2017
• First Posted (ACTUAL): December 18, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 9, 2021
• Last Update Submitted That Met QC Criteria: March 8, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Hypertension; Cardiovascular Disease; Skin; Oxidative Stress; Dairy; Diet; Cheese; Blood Pressure; Sodium; Microcirculation; Nitric Oxide; Nitroglycerin; Superoxide; Flow Mediated Vasodilation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Cholinergic Agents; Cholinergic Agonists; Nitroglycerin; Acetylcholine
• Other Study ID Numbers: STUDY4340; 129552 (OTHER: FDA)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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