Clinical Trial

Vascular Function in Health and Disease

Study Description

: Vascular Function in Health and Disease

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.

Location

Locations Selected Location

Methods

Pharmaceutical medication involved Pharmaceutical medication involved
Patients and healthy individuals accepted Patients and healthy individuals accepted

Maximum Exercise Tests

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

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

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.

Drug - BQ-123

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).

Drug - Fexofenadine, Ranitidine

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).

Angiotensin-II, Valsartan

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).

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

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).

Drug - BQ-123, MitoQ, BH4

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.

Additional Information

Official Study Title

Vascular Function in Health & Disease: Rehabilitation for Hypertension; Exercise and Skeletal Muscle Afferent Feedback

Clinical Trial ID

NCT02966665

ParticipAid ID

7axB3d