Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.

Detailed Description
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Flow-Mediated Dilation (FMD) - Subjects will lie in the supine position for 20 minutes to obtain hemodynamic steady state. A blood pressure cuff (Hokanson) will be placed around the forearm (distal to the Doppler transducer) and rapidly inflated to 250 mmHg for 5 minutes (circulatory arrest). Simultaneous ultrasound images of the vessel (B-mode) and Doppler waveforms will be collected 10 seconds prior to and for 2 minutes following deflation of the cuff. All B-mode images will be analyzed using automated edge detection software (Medical Imaging Applications), while intensity weighted velocity spectra segments will be saved to the GE Logiq 7 hard drive for off-line blood velocity waveform analysis. P.I. has utilized the traditional method of brachial artery flow-mediated dilation (FMD) induced by reactive hyperemia to assess vascular endothelial function in populations ranging from young healthy adults to older adults with pathological conditions. Spygmocor - Pulse Wave Velocity (PWV) - A Spygmocor® device will be used at baseline and following each protocol to assess PWV. PWV analysis provides a non-invasive assessment of arterial stiffness. Increased arterial stiffness is known to be associated with cardiovascular disease. The participant is required to lie in a resting position for approximately 30-45 minutes. The research assistant will place ECG electrode sensors at the carotid, femoral, radial and distal artery locations. A highly sensitive pen-like device, called a tonometer, is then gently applied to record the velocity of the blood flow between each of the points.

Official Title
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Regulation of Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease: A Mechanistic Approach

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tetrahydrobiopterin (BH4)
* Dietary Supplement: Antioxidant Cocktail


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with COPD (GOLD stages II-IV) and matched healthy controls Caucasian or African American Both men and women Current and former smokers Exclusion Criteria: GOLD Stage I Clinical diagnosis of heart disease, hypertension, or metabolic disease Vasoactive medications (i.e. nitrates, beta-blockers, ACE inhibitors, Viagra, etc.) Pulmonary hypertension Hypothyroidism Hyper-homocysteinemia Interstitial lung disease Phenylketonuria Pregnancy Sleep apnea Anemia Raynod's phenomenon Gangrene of the digits History of low platelets or coagulopathies Aspirin sensitivity or allergy

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COPD Patients<br>Patients with COPD AOC protocol: Brachial artery flow-mediated dilation, direct assessment of oxidative stress via EPR spectroscopy (O2-) and biomarkers of oxidative stress (8-isoprostane, LH, SOD) will be assessed at baseline and 2 hours following ingestion of a single oral antioxidant cocktail (1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid.) Antioxidant Cocktail: 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid BH4 protocol: Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following an increase in nitric oxide bioavailability after administering a single dose = 5 mg/kg of Tetrahydrobiopterin (BH4) | Drug: Tetrahydrobiopterin (BH4)<br>* single dose = 5 mg/kg<br>* Other names: Kuvan (Sapropterin Dihydrochloride);Dietary Supplement: Antioxidant Cocktail<br>* 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid<br>|
| Experimental: Controls<br>Healthy age- and sex- matched controls AOC protocol: Brachial artery flow-mediated dilation, direct assessment of oxidative stress via EPR spectroscopy (O2-) and biomarkers of oxidative stress (8-isoprostane, LH, SOD) will be assessed at baseline and 2 hours following ingestion of a single oral antioxidant cocktail (1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid.) Antioxidant Cocktail: 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid BH4 protocol: Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following an increase in nitric oxide bioavailability after administering a single dose = 5 mg/kg of Tetrahydrobiopterin (BH4) | Drug: Tetrahydrobiopterin (BH4)<br>* single dose = 5 mg/kg<br>* Other names: Kuvan (Sapropterin Dihydrochloride);Dietary Supplement: Antioxidant Cocktail<br>* 1g of vitamin C, 600 IU of vitamin E, and 600 mg of alpha-lipoic acid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow-Mediated Dilation (FMD) | Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function at baseline and several hours after each experimental intervention. | Post FMD was taken approximately 110 min after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulse Wave Velocity | A measure of vascular stiffness at baseline and several hours after each experimental intervention. | Post PWV was taken approximately 90 min after baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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flow-mediated dilation, arterial stiffness, intima-media thickness, pulse wave velocity, dual energy x-ray absorptiometry, inflammatory markers, blood lipids, tetrahydrobiopterin, body mass index, hemoglobin A1c, complete blood count, oxidative stress biomarkers, pulmonary function test, lung, COPD