: Vascular Function in Health and Disease
| Status: | Recruiting |
|---|---|
| Conditions: | Chronic Obstructive Pulmonary Disease, High Blood Pressure (Hypertension), Cardiology, Pulmonary |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/17/2018 |
| Start Date: | September 2008 |
| End Date: | August 2020 |
| Contact: | Maydeen Ogara |
| Email: | maydeen.ogara@hsc.utah.edu |
| Phone: | 801-584-2522 |
Vascular Function in Health & Disease: Rehabilitation for Hypertension; Exercise and Skeletal Muscle Afferent Feedback
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.
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.
Angiotensin-II (ANG-II) is the end-product of the renin-angiotensin cascade, and acts as a
potent endogenous vasoconstrictor through binding to the angiotensin receptor (AT1) on
arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma
renin activity accompanied by decrements in circulating ANG-II and an increase in AT1
receptor density. However, the functional consequence of this age-related adaptation of the
renin-angiotensin system (RAS) on the peripheral circulation is not well understood.
Likewise, in recent years it has become apparent that cardiovascular disease is a major cause
of morbidity in COPD, which may be related to vascular dysfunction and associated adoption of
a sedentary lifestyle. In these patients, changes in RAS activity have been linked to
peripheral vascular dysfunction, with compelling evidence for improvements in peripheral
oxygen use following angiotensin-converting enzyme (ACE) inhibition. Like the aging
population, systematic studies evaluating AT1 receptor sensitivity and the efficacy of AT1
receptor blockade on peripheral hemodynamics have not been undertaken.
The ubiquitous substance nitric oxide (NO) is now recognized as a key pathway for
endothelium-dependent vasodilation, with the bioavailability of NO serving as an indicator
for overall vascular health. Cardiac risk factors have been shown to cause impairment in
endothelial vasodilator function in both the peripheral and coronary arteries. Coronary
vascular dysfunction is an important phase in atherogenesis and is associated with myocardial
ischemia. Furthermore, peripheral vascular function has been linked to coronary vascular
dysfunction which could have important clinical implications in terms of health screening.
Impaired endothelium-dependent vasodilation has been associated with the elderly, patients
with COPD, and most cardiovascular diseases including pulmonary hypertension, and heart
failure (HF), though the functional consequence of this adaptation on peripheral blood flow
regulation remains unclear. Thus, we propose the use of a compound which inhibits the enzyme
responsible for NO production in endothelial cells, N-monomethyl-L-arginine (L-NMMA), to
temporarily block production of NO and thus determine the importance of this pathway at rest
and during physical activity. Additionally, we propose the use of acetylcholine (Ach) to
determine endothelial-dependent vasodilation and sodium nitroprusside (SNP) and nitroglycerin
(NTG) to determine the endothelial-independent vasodilation in the coronary arteries and the
periphery. Oxidative stress associated with aging has been shown to reduce vascular function
and antioxidant supplementation restores vascular function to levels that are
indistinguishable from healthy young adults. The manner by which this improvement in vascular
function occurs is not known by may be acting through a NO dependent mechanism.
Histamine has been reported to mediate sustained post-exercise vasodilation through
histamine-1 (H1) and histamine-2 (H2) receptor activity, which results in a ~50% elevation in
femoral artery blood flow (above resting levels) that lasts for more than 100 minutes after a
single bout of moderate-intensity dynamic exercise. Vasodilation can be markedly reduced by
giving either fexofenadine (Allegra, a selective H1-receptor antagonist) or ranitidine
(Zantac, a selective H2-receptor antagonist). The combination of H1/H2 blockade abolishes
~80% of the post-exercise vasodilation seen after whole-body exercise such as cycling and
this observation has been observed in multiple studies in young sedentary, recreationally
active, and endurance trained men and women. The impact of histamine on the post-exercise
vasodilatory response is substantial; however, the role of H1/H2 receptors in regulating
skeletal muscle blood flow during exercise is unknown. Thus, we intend to investigate the
role of H1/H2 receptors in the regulation of skeletal muscle blood during exercise as this
may be an important pathway in age and disease related reductions in blood flow during
exercise.
Exercise training and rehabilitation can be used as an alternative approach to combat the
deleterious effects oxidative stress on aging and disease. An effective exercise training
intervention can decrease sympathetic nervous system activity, improve arterial compliance
and vascular endothelial function, and alter the pro- and antioxidant balance resulting in
improved endogenous antioxidant defense mechanisms. Moreover, exercise training concomitantly
improves musculoskeletal strength and function, glucose regulation and insulin sensitivity,
cardiovascular function, body composition, blood chemistry (decreased triglyceride and
cholesterol levels), and overall well-being. The physiologic effect of an exercise
rehabilitation program in diseases such as COPD, and pulmonary arterial hypertension (PAH) is
incompletely understood. However, recent studies suggest that exercise training in this
patient population is well tolerated and associated with clinically significant physiologic
improvements as well as improvements in various quality of life scores.
A unique feature of the proposed studies identified herein is the inclusion of a novel
methodological approach to comprehensively evaluate the functional outcome of the proposed
pharmacologic interventions. The recent development of a unique combination of nuclear
magnetic resonance (NMR) techniques by members of our group enables near-simultaneous
measurements of both muscle perfusion and metabolism in vivo. The arterial spin labeling
(ASL) technique allows the measurement of both spatially and temporally resolved
quantification of perfusion, while the kinetics of phosphocreatine (PCr) depletion and
recovery provide high resolution measurements of muscle energetics. The interweaving of these
imaging and spectroscopic modules provides the opportunity for determination of skeletal
muscle perfusion and metabolism kinetics during and following the stress of physical
exercise. Thus, this NMR-based approach, combined with direct measures of muscle fatigue,
offers the potential to further define the individual and collective contribution of these
variables to the attenuated limb blood flow in the elderly and in patients with COPD and PAH.
We propose that each of these pathways outlined above represent an avenue by which vascular
function is compromised in the elderly and in patients with COPD, PAH and cardiovascular
disease. However, because these pathways are not mutually exclusive, the proposed studies are
designed to systematically evaluate hemodynamic responses to intra-arterial or intravenous
administration of pharmacologic agents specific for the AT1 receptor (ANG-II and Diovan, AT1
agonist and antagonist, respectively), the Endothelin receptor Type-A (ETA receptor) (BQ-123,
ETA antagonist), and the NO pathway (L-NMMA, Ach, and SNP) both before and after exercise
training.
potent endogenous vasoconstrictor through binding to the angiotensin receptor (AT1) on
arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma
renin activity accompanied by decrements in circulating ANG-II and an increase in AT1
receptor density. However, the functional consequence of this age-related adaptation of the
renin-angiotensin system (RAS) on the peripheral circulation is not well understood.
Likewise, in recent years it has become apparent that cardiovascular disease is a major cause
of morbidity in COPD, which may be related to vascular dysfunction and associated adoption of
a sedentary lifestyle. In these patients, changes in RAS activity have been linked to
peripheral vascular dysfunction, with compelling evidence for improvements in peripheral
oxygen use following angiotensin-converting enzyme (ACE) inhibition. Like the aging
population, systematic studies evaluating AT1 receptor sensitivity and the efficacy of AT1
receptor blockade on peripheral hemodynamics have not been undertaken.
The ubiquitous substance nitric oxide (NO) is now recognized as a key pathway for
endothelium-dependent vasodilation, with the bioavailability of NO serving as an indicator
for overall vascular health. Cardiac risk factors have been shown to cause impairment in
endothelial vasodilator function in both the peripheral and coronary arteries. Coronary
vascular dysfunction is an important phase in atherogenesis and is associated with myocardial
ischemia. Furthermore, peripheral vascular function has been linked to coronary vascular
dysfunction which could have important clinical implications in terms of health screening.
Impaired endothelium-dependent vasodilation has been associated with the elderly, patients
with COPD, and most cardiovascular diseases including pulmonary hypertension, and heart
failure (HF), though the functional consequence of this adaptation on peripheral blood flow
regulation remains unclear. Thus, we propose the use of a compound which inhibits the enzyme
responsible for NO production in endothelial cells, N-monomethyl-L-arginine (L-NMMA), to
temporarily block production of NO and thus determine the importance of this pathway at rest
and during physical activity. Additionally, we propose the use of acetylcholine (Ach) to
determine endothelial-dependent vasodilation and sodium nitroprusside (SNP) and nitroglycerin
(NTG) to determine the endothelial-independent vasodilation in the coronary arteries and the
periphery. Oxidative stress associated with aging has been shown to reduce vascular function
and antioxidant supplementation restores vascular function to levels that are
indistinguishable from healthy young adults. The manner by which this improvement in vascular
function occurs is not known by may be acting through a NO dependent mechanism.
Histamine has been reported to mediate sustained post-exercise vasodilation through
histamine-1 (H1) and histamine-2 (H2) receptor activity, which results in a ~50% elevation in
femoral artery blood flow (above resting levels) that lasts for more than 100 minutes after a
single bout of moderate-intensity dynamic exercise. Vasodilation can be markedly reduced by
giving either fexofenadine (Allegra, a selective H1-receptor antagonist) or ranitidine
(Zantac, a selective H2-receptor antagonist). The combination of H1/H2 blockade abolishes
~80% of the post-exercise vasodilation seen after whole-body exercise such as cycling and
this observation has been observed in multiple studies in young sedentary, recreationally
active, and endurance trained men and women. The impact of histamine on the post-exercise
vasodilatory response is substantial; however, the role of H1/H2 receptors in regulating
skeletal muscle blood flow during exercise is unknown. Thus, we intend to investigate the
role of H1/H2 receptors in the regulation of skeletal muscle blood during exercise as this
may be an important pathway in age and disease related reductions in blood flow during
exercise.
Exercise training and rehabilitation can be used as an alternative approach to combat the
deleterious effects oxidative stress on aging and disease. An effective exercise training
intervention can decrease sympathetic nervous system activity, improve arterial compliance
and vascular endothelial function, and alter the pro- and antioxidant balance resulting in
improved endogenous antioxidant defense mechanisms. Moreover, exercise training concomitantly
improves musculoskeletal strength and function, glucose regulation and insulin sensitivity,
cardiovascular function, body composition, blood chemistry (decreased triglyceride and
cholesterol levels), and overall well-being. The physiologic effect of an exercise
rehabilitation program in diseases such as COPD, and pulmonary arterial hypertension (PAH) is
incompletely understood. However, recent studies suggest that exercise training in this
patient population is well tolerated and associated with clinically significant physiologic
improvements as well as improvements in various quality of life scores.
A unique feature of the proposed studies identified herein is the inclusion of a novel
methodological approach to comprehensively evaluate the functional outcome of the proposed
pharmacologic interventions. The recent development of a unique combination of nuclear
magnetic resonance (NMR) techniques by members of our group enables near-simultaneous
measurements of both muscle perfusion and metabolism in vivo. The arterial spin labeling
(ASL) technique allows the measurement of both spatially and temporally resolved
quantification of perfusion, while the kinetics of phosphocreatine (PCr) depletion and
recovery provide high resolution measurements of muscle energetics. The interweaving of these
imaging and spectroscopic modules provides the opportunity for determination of skeletal
muscle perfusion and metabolism kinetics during and following the stress of physical
exercise. Thus, this NMR-based approach, combined with direct measures of muscle fatigue,
offers the potential to further define the individual and collective contribution of these
variables to the attenuated limb blood flow in the elderly and in patients with COPD and PAH.
We propose that each of these pathways outlined above represent an avenue by which vascular
function is compromised in the elderly and in patients with COPD, PAH and cardiovascular
disease. However, because these pathways are not mutually exclusive, the proposed studies are
designed to systematically evaluate hemodynamic responses to intra-arterial or intravenous
administration of pharmacologic agents specific for the AT1 receptor (ANG-II and Diovan, AT1
agonist and antagonist, respectively), the Endothelin receptor Type-A (ETA receptor) (BQ-123,
ETA antagonist), and the NO pathway (L-NMMA, Ach, and SNP) both before and after exercise
training.
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
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