: Vascular Function in Health and Disease

NCT02966665 | Recruiting Phase 1

• 1 other identifier: IRB_00030810
• Study Type: interventional
• Target: 420
• Locations: 1 country
• Sites: 1

Brief Summary

Many control mechanisms exist which successfully match the supply of blood with the metabolic demand of various tissues under wide-ranging conditions. One primary regulator of vasomotion and thus perfusion to the muscle tissue is the host of chemical factors originating from the vascular endothelium and the muscle tissue, which collectively sets the level of vascular tone. With advancing age and in many disease states, deleterious adaptations in the production and sensitivity of these vasodilator and vasoconstrictor substances may be observed, leading to a reduction in skeletal muscle blood flow and compromised perfusion to the muscle tissue. Adequate perfusion is particularly important during exercise to meet the increased metabolic demand of the exercising tissue, and thus any condition that reduces tissue perfusion may limit the capacity for physical activity. As it is now well established that regular physical activity is a key component in maintaining cardiovascular health with advancing age, there is a clear need for further studies in populations where vascular dysfunction is compromised, with the goal of identifying the mechanisms responsible for the dysfunction and exploring whether these maladaptations may be remediable. Thus, to better understand the etiology of these vascular adaptations in health and disease, the current proposal is designed to study changes in vascular function with advancing age, and also examine peripheral vascular changes in patients suffering from chronic obstructive pulmonary disease (COPD), Sepsis, Pulmonary Hypertension, and cardiovascular disease. While there are clearly a host of vasoactive substances which collectively act to govern vasoconstriction both at rest and during exercise, four specific pathways that may be implicated have been identified in these populations: Angiotensin-II (ANG-II), Endothelin-1 (ET-1), Nitric Oxide (NO), and oxidative stress.

Conditions

Chronic Obstructive Pulmonary Disease; Pulmonary Artery Hypertension; Heart Failure; Hypertension

Outcome Measures

Primary Outcomes (1)

• Change in Limb Blood Flow

  Change in local limb blood flow as measured by ultrasound Doppler in units of milliliters per minute (mL/min) from baseline to up to 1 hour following study interventions

  Baseline and 1 hour

Secondary Outcomes (3)

• Change in Blood Pressure

  Baseline and 1 hour

• Change in Maximum Exercise Capacity

  Baseline and 1 hour

• Change in Peak Rate of Mitochondrial Adenosine Triphosphate (ATP) Synthesis

  Baseline and 1 hour

Study Arms (7)

Healthy Young Volunteers (18-30 years)

EXPERIMENTAL

Healthy volunteers between the ages of 18 and 30 years with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Healthy Older Controls (over 65 years)

EXPERIMENTAL

Healthy volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Coronary Angiography patients

EXPERIMENTAL

Patients undergoing routine coronary angiography, but who do not require intracoronary procedures or have history of myocardial disease, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Chronic Obstructive Pulmonary Disease patients

EXPERIMENTAL

Patients diagnosed with mild to moderate COPD, but not severe COPD patients, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Pulmonary Arterial Hypertension patients

EXPERIMENTAL

Patients with idiopathic or heritable Group 1 pulmonary arterial hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Heart Failure patients

EXPERIMENTAL

Patients with Class I - III New York Heart Association symptoms of Heart Failure who are not anemic or taking medications that affect blood clotting, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Hypertension patients

EXPERIMENTAL

Patients with chronic high blood pressure, but with less than severe hypertension, administered various treatments to assess their effect on blood flow and metabolic demand of tissues under wide-ranging conditions, including Maximum Exercise Tests, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid, L-Ascorbate, BQ-123, Fexofenadine, Ranitidine, Angiotensin-II, Valsartan, Acetylcholine, Sodium Nitroprusside, Norepinephrine, Phentolamine and MitoQ.

Other: Maximum Exercise Tests; Drug: BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate; Drug: BQ-123; Drug: Fexofenadine, Ranitidine; Other: Angiotensin-II, Valsartan; Drug: Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine; Drug: BQ-123, MitoQ, BH4

Interventions

Maximum Exercise Tests OTHER

Graded exercise test to volitional exhaustion (stationary bike or treadmill), maximal handgrip test, maximal leg extension test, and maximal plantar flexion test.

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate DRUG

Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, passive leg movement test, exercise bouts, electromyography and exercise training regimen at baseline and following treatment with Nitric Oxide blockade via infusion of N-monomethyl-L-arginine (L-NMMA) (0.4 mg/kg/min), antioxidant cocktail (Vitamin C, Vitamin E, alpha-lipoic acid) ingestion, L-ascorbate injection, BH4 ingestion.

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

BQ-123 DRUG

Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with endothelin-1 receptor antagonist BQ-123 (D-tryptamine-D-aspartic acid-L-proline-D-valine-L-leucine).

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

Fexofenadine, Ranitidine DRUG

Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test and exercise bouts at baseline and following treatment with Histamine H1 receptor antagonist fexofenadine (Allegra) and Histamine H2 receptor antagonist ranitidine (Zantac).

Also known as: Allegra, Zantac

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

Angiotensin-II, Valsartan OTHER

Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement, and exercise bouts at baseline and following treatment with Angiotensin-II receptor agonist (angiotensin-II) and antagonist Valsartan (Diovan).

Also known as: Diovan

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine DRUG

Catheter placement in femoral artery and femoral vein; resting measurements of blood pressure, heart rate and blood flow; flow mediated vasodilation test, muscle sympathetic nerve activity measurement; vasodilation with nitroglycerin followed by Angiotensin-II and Alpha Adrenergic blockade with infusions of Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine and Phentolamine (Regitine).

Also known as: Regitine

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

BQ-123, MitoQ, BH4 DRUG

Catheter placement in femoral artery and femoral vein and muscle biopsy; Nuclear Magnetic Resonance (NMR) scanning and exercise bouts at baseline and following treatment with BQ-123 with or without oral mitochondria-targeted antioxidant (MitoQ) or oral BH4.

Chronic Obstructive Pulmonary Disease patients; Coronary Angiography patients; Healthy Older Controls (over 65 years); Healthy Young Volunteers (18-30 years); Heart Failure patients; Hypertension patients; Pulmonary Arterial Hypertension patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy Young Volunteers: 18-30 years of age with no diseases or conditions that would affect their participation in the study
• Healthy Older Controls: volunteers 65 years of age or older with no diseases or conditions that would affect their participation in the study
• Coronary Angiography subjects: patients undergoing routine coronary angiography
• Chronic Obstructive Pulmonary Disease subjects: patients diagnosed with mild to moderate COPD
• Pulmonary Arterial Hypertension subjects: patients with idiopathic or heritable Group 1 pulmonary arterial hypertension
• Heart Failure subjects: patients with Class I, II or III New York Heart Association symptoms of Heart Failure
• Hypertension subjects: patients diagnosed with chronic high blood pressure

You may not qualify if:

• Severe COPD (use of supplemental oxygen, or have a one-second forced expiratory volume of less than 30% predicted)
• History of myocardial infarction
• History of percutaneous coronary revascularization
• History of coronary artery bypass grafting
• Unstable angina pectoris
• History of variant angina
• Ejection fraction \< 50%
• Significant renal disease (Glomerular Filtration Rate \< 50 mL/min/1.73m2)
• Subjects whose medical care or safety may be at risk from undergoing a Magnetic Resonance Imaging examination (e.g. pacemaker, metal implants, certain types of heart valves)
• Subject is pregnant
• Subject has physical ailments (other than COPD, PAH, HF, or hypertension) that would prevent them from study participation in the judgment of the investigator

Sponsors & Collaborators

• Russell Richardson: lead

Study Sites (1)

George E Wahlen VA Medical Center

Salt Lake City, Utah, 84132, United States

RECRUITING

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension

Interventions

omega-N-Methylarginine; Ascorbic Acid; Vitamin E; Thioctic Acid; cyclo(Trp-Asp-Pro-Val-Leu); fexofenadine; Ranitidine; Angiotensin I; Valsartan; Acetylcholine; Nitroprusside; Norepinephrine; Phentolamine; mitoquinone

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hypertension, Pulmonary; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiophenes; Sulfur Compounds; Coenzymes; Enzymes and Coenzymes; Fatty Acids; Lipids; Furans; Angiotensins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Oligopeptides; Nerve Tissue Proteins; Proteins; Autacoids; Inflammation Mediators; Biological Factors; Tetrazoles; Azoles; Valine; Amino Acids, Branched-Chain; Biogenic Amines; Amines; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Ethanolamines; Amino Alcohols; Alcohols; Biogenic Monoamines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles

Study Officials

• Russell Richardson, Ph.D.

  George E Wahlen VA Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maydeen Ogara

CONTACT

801-584-2522; maydeen.ogara@hsc.utah.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Ph.D.

Study Record Dates

• First Submitted: October 19, 2016
• First Posted: November 17, 2016
• Study Start: September 1, 2008
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)