Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease (COPD)

Not Applicable

Completed

Conditions: Pulmonary Disease, Chronic Obstructive

Interventions: Drug: Tetrahydrobiopterin (BH4)
Dietary Supplement: Antioxidant Cocktail

Registration Number: NCT01398943

Lead Sponsor: Augusta University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
COPD Patients	Tetrahydrobiopterin (BH4)	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)
COPD Patients	Antioxidant Cocktail	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)
Controls	Tetrahydrobiopterin (BH4)	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)
Controls	Antioxidant Cocktail	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)

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Pulse Wave Velocity	Post PWV was taken approximately 90 min after baseline	A measure of vascular stiffness at baseline and several hours after each experimental intervention.