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Dietary Nitrate and Nitrite to Increase Nitric Oxide in Patients With Coronary Artery Disease

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ClinicalTrials.gov Identifier: NCT00069654
Recruitment Status : Completed
First Posted : September 30, 2003
Last Update Posted : July 2, 2017
Information provided by:
National Institutes of Health Clinical Center (CC)

Brief Summary:

This study will determine whether dietary nitrates and nitrites can produce nitric oxide in the body and dilate blood vessels in patients with coronary artery disease. Nitric oxide is normally made by endothelial cells that line blood vessels. It plays an important role in maintaining the normal function of arteries by keeping them open and preventing damage from substances such as cholesterol in the blood stream. Coronary artery disease is caused by atherosclerosis (hardening of the arteries or build-up of cholesterol and scar tissue within the walls of the arteries). Once arteries become clogged, the ability of the endothelium to produce nitric oxide diminishes considerably and may speed up the disease process, leading to shortness of breath, chest pain, and an increased risk of heart attack or stroke.

Patients 21 years of age and older with coronary artery disease may be eligible for this study. Participants will have a medical history and physical examination, electrocardiogram (recording of the electrical activity of the heart), echocardiogram (ultrasound test of the heart), treadmill exercise stress test (see below), and will meet with a dietitian. They will be hospitalized at the NIH Clinical Center on two occasions. For 1 week before each admission, they will follow a diet prescribed by an NIH nutritionist. The diet before one admission will be high in nitrates and nitrites, and the diet before the other admission will be low in nitrates and nitrites. Each admission will last 4 days, during which participants will undergo the following tests:

  • Forearm blood flow study: Small tubes are placed in the artery and vein at the inside of the elbow of the dominant arm (right- or left-handed) and a small tube is placed in a vein of the other arm. The tubes are used for infusing saline (salt water) and for drawing blood samples. A pressure cuff is placed around the upper part of the dominant arm, and a rubber band device called a strain gauge is also placed around the arm to measure blood flow. When the cuff is inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the flow. Maximum grip-strength of the dominant arm is measured with a dynamometer. Forearm blood flow is measured and blood samples are drawn at the following times: 20 minutes after the tubes are placed; during a hand-grip exercise; and 4 minutes after the exercise is completed.
  • Brachial artery reactivity study: This test measures h...

Condition or disease Intervention/treatment Phase
Coronary Arteriosclerosis Procedure: Forearm blood flow study Procedure: Brachial artery reactivity study Procedure: Treadmill exercise test Phase 2

Detailed Description:
Nitric oxide (NO) is a soluable gas continuously synthesized by the endothelium that contributes importantly to vasodilator tone of the coronary and systemic circulations by activating guanylyl cyclase in vascular smooth muscle, causing relaxation. Patients with coronary artery disease, however, have deficient synthesis or increased degradation of NO due to endothelial damage or dysfunction. Reduced NO could contribute to symptoms and progression of coronary artery disease through vasoconstriction, platelet activation, inflammatory cell attachment to the arterial wall, and increased growth of cellular elements of the vessel wall. We have recently determined that nitrite, formed by the auto-oxidation of NO, can be converted to bioactive NO, in part through reactions with deoxyheme proteins that exist not only in red blood cells, but also within the vessel wall. An alternative source of bioactive NO may be via the diet, as nitrates reductases present in oral bacteria. Nitrite may then be converted to NO within the acidic environment in the stomach and absorbed into the bloodstream, or absorbed directly and converted to NO in the bloodstream via reaction with deoxyheme proteins. This study is designed to determine the contribution of daily nitrate/nitrite to NO adducts in blood and to vascular dilator tone assessed directly in the forearm and indirectly through treadmill exercise testing. Findings in this study may have important clinical implications not only in coronary artery disease, but also in other conditions associated with regional endothelial dysfunction and reduced endothelial NO bioactivity (e.g., hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, estrogen deficiency), and possibly account for the cardiovascular benefit of diets rich in vegetables shown in epidemiological survey studies.

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Study Type : Interventional  (Clinical Trial)
Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Dietary Nitrate/Nitrite as Sources of Bioactive Nitric Oxide in Patients With Coronary Artery Disease
Study Start Date : September 25, 2003
Actual Primary Completion Date : May 18, 2009

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. Comparison of forearm blood flow during exercise after 3 days of the nitrate-nitrite-enriched diet to forearm blood flow during exercise after 3 days of the nitrate/nitrite-restricted diet. [ Time Frame: Measured on day 4 of the nitrite/nitrate enriched and restricted diet ]

Secondary Outcome Measures :
  1. Comparison of effects of high versus low nitrate/nitrite diets on exercise forearm blood flow between the two cohorts of patients. [ Time Frame: Measured on day 4 of the nitrite/nitrate enriched and restricted diet. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   22 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Adults older than 21 years.

Coronary artery disease established by angiography.

No myocardial infarction within 1 month.

Left ventricular ejection fraction greater than 30%.

No congestive heart failure symptoms within 2 months.

Subject provides written, informed consent.


Significant structural heart disease (e.g. hypertrophic or dilated cardiomyopathy, valvular heart disease) as determined by echocardiography.

Subject physically unable to perform treadmill exercise due to neurologic or orthopedic conditions.

Hypersensitivity to organ nitrates.

Insulin-dependant diabetes mellitus.

Coumadin therapy (because of vitamin K content of green leafy vegetables).

Women of childbearing age unless recent pregnancy test is negative.

Lactating women.

Unwillingness to adhere to dietary requirements or allergy to necessary components of diets, as determined during interview by the dietician.

Surgical or disease-related diminished acid secretion.

Significant non-cardiac disease.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00069654

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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Responsible Party: Mark T. Gladwin, M.D./National Heart, Lung, and Blood Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00069654    
Other Study ID Numbers: 030312
First Posted: September 30, 2003    Key Record Dates
Last Update Posted: July 2, 2017
Last Verified: May 18, 2009
Keywords provided by National Institutes of Health Clinical Center (CC):
Coronary Artery Disease
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases