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.
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
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
Parallel
Maximum Exercise Tests
Other interventionGraded exercise test to volitional exhaustion (stationary bike or treadmill), maximal handgrip test, maximal leg extension test, and maximal plantar flexion test.
BH4, L-NMMA, Vitamin C, Vitamin E, α-Lipoic Acid and L-Ascorbate
DrugCatheter 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.
BQ-123
DrugCatheter 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).
Fexofenadine, Ranitidine
DrugCatheter 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).
Angiotensin-II, Valsartan
Other interventionCatheter 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).
Acetylcholine, Sodium Nitroprusside, Angiotensin-II, Norepinephrine, Phentolamine
DrugCatheter 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).
BQ-123, MitoQ, BH4
DrugCatheter 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.
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Treatment groupsSee each treatment group below.
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
Change in Blood Pressure
Change in local limb blood pressure measured in millimeters of mercury (mmHg) from baseline to up to 1 hour following study interventions
Change in Maximum Exercise Capacity
Change in maximal exercise capacity - handgrip strength measured by dynamometer in units of kilograms from baseline to up to 1 hour following study interventions
Change in Peak Rate of Mitochondrial Adenosine Triphosphate (ATP) Synthesis
Change in muscle peak rate of mitochondrial ATP synthesis as measured by 31P-magnetic resonance spectroscopy (31P-MRS) from baseline up to 1 hour following study interventions
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D. Walter Wray
Lead sponsor
University of Utah
Sponsor institution
