Nearly 37% of all Veterans are clinically hypertensive, making hypertension the most common medical condition in the VA Health Care System. Importantly, of the 67 million Americans diagnosed with hypertension less than half are being effectively treated for their condition4. Hypertension constitutes a major risk factor for cardiovascular disease and when left untreated leads to the development of heart failure, coronary heart disease, peripheral artery disease, stroke, and renal disease5, 6. Exercise and regular physical activity are considered the cornerstones of prevention and management of hypertension 5-7. However, individuals with hypertension exhibit exercise intolerance characterized by impaired skeletal muscle blood flow and heightened afferent fiber sensitivity leading to an exaggerated or greater than normal physiologic increase in blood pressure during exercise (i.e. exercise pressor reflex or EPR)8-10. This imbalance between the beneficial effects of exercise and exercise intolerance creates an interesting paradox, the causes and consequences of which are poorly understood. The etiology of hypertension is undoubtedly complex, however a common denominator in this condition, elevated oxidative stress, may contribute to impaired muscle blood flow and heightened skeletal muscle afferent feedback leading to the exaggerated EPR11-13. Previous work from our laboratory and others suggests that elevated oxidative stress associated with aging impairs muscle blood flow 14, 15. Additionally, free radicals, the initiators of oxidative stress, can diretly stimulate skeletal muscle afferent fibers leading to the exaggerated EPR11. Importantly, the role of oxidative stress in regulating muscle blood flow and afferent fiber function in human hypertension has not been determined. Preliminary studies support a significant role of oxidative stress in impairing muscle blood flow and contributing to the exaggerated EPR in hypertension. With this information as context two aims are proposed that will systematically identify the consequences of elevated oxidative stress in hypertension.
Specific Aim 1 will determine the consequences of oxidative stress by examining how elevated free radicals contribute to heightened skeletal muscle afferent feedback and impaired muscle blood flow during exercise in hypertension leading to the exaggerated EPR. Additionally, vascular endothelial cells collected from an antecubital vein will provide novel insight regarding the endothelium as potential source of elevated oxidative stress in hypertension.
Specific Aim 2 will determine the effectiveness of combined antioxidant therapy and exercise rehabilitation in the treatment of hypertension. The overall goal of this proposal is to provide novel information regarding the role of oxidative stres as a critical regulator of cardiovascular and hemodynamic responses to exercise in hypertension. By identifying potential causes and consequences of oxidative stress, important insight will be gained facilitating the development of novel approaches and therapeutic strategies for the treatment of hypertension. Importantly, the practical applications tested in these studies (i.e. antioxidant treatment and combined exercise rehabilitation) are designed to identify and document effective countermeasures to aid in the treatment and management of hypertension allowing for the safe performance of exercise in a large number of Veterans.

Public Health Relevance

Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. However, individuals with hypertension have impaired muscle blood flow and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to exercise intolerance and increased risk of stroke and heart attack. The cause of these impairments is not known, but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role. Two aims are proposed; Aim 1 will identify the physiological consequences of elevated oxidative stress in hypertension, and Aim 2 will utilize an antioxidant treatment to ameliorate the effects o an exaggerated EPR allowing the safe performance of a clinical exercise rehabilitation program which will then, itself, attenuate the EPR and reduce hypertension.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Career Development Program - Panel II (RRD9)
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VA Salt Lake City Healthcare System
Salt Lake City
United States
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Trinity, Joel D; Layec, Gwenael; Hart, Corey R et al. (2018) Sex-specific impact of aging on the blood pressure response to exercise. Am J Physiol Heart Circ Physiol 314:H95-H104
Broxterman, Ryan M; Trinity, Joel D; Gifford, Jayson R et al. (2017) Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol (1985) 123:1468-1476
Layec, Gwenael; Hart, Corey R; Trinity, Joel D et al. (2017) Oxygen delivery and the restoration of the muscle energetic balance following exercise: implications for delayed muscle recovery in patients with COPD. Am J Physiol Endocrinol Metab 313:E94-E104
Venturelli, Massimo; Layec, Gwenael; Trinity, Joel et al. (2017) Single passive leg movement-induced hyperemia: a simple vascular function assessment without a chronotropic response. J Appl Physiol (1985) 122:28-37
Layec, Gwenael; Trinity, Joel D; Hart, Corey R et al. (2016) Evidence of a metabolic reserve in the skeletal muscle of elderly people. Aging (Albany NY) 9:52-67
Trinity, Joel D; Wray, D Walter; Witman, Melissa A H et al. (2016) Ascorbic acid improves brachial artery vasodilation during progressive handgrip exercise in the elderly through a nitric oxide-mediated mechanism. Am J Physiol Heart Circ Physiol 310:H765-74
Trinity, Joel D; Broxterman, Ryan M; Richardson, Russell S (2016) Regulation of exercise blood flow: Role of free radicals. Free Radic Biol Med 98:90-102
Gifford, Jayson R; Garten, Ryan S; Nelson, Ashley D et al. (2016) Symmorphosis and skeletal muscle V?O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human. J Physiol 594:1741-51
Trinity, Joel D; Barrett-O'Keefe, Zachary; Ives, Stephen J et al. (2016) Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis. J Hypertens 34:266-73
Groot, H Jonathan; Trinity, Joel D; Layec, Gwenael et al. (2015) The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure. J Physiol 593:3917-28

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