Peripheral vascular endothelial function declines progressively with advancing age in humans, and is further impaired in patients with obstructive sleep apnea (OSA), increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Further, the sympathoadrenal system is a key regulator of vascular tone, particularly during stress conditions in humans. Our preliminary data indicates that healthy aging is associated with impaired peripheral vascular control during acute reductions in arterial oxygen content (hypoxia), a physiological and pathophysiological stress that evokes reflex increases in sympathoadrenal activity as well as the synthesis of local endothelium-derived vasoactive factors. Older OSA patients experience frequent and recurrent systemic hypoxia and are at elevated risk for cardiovascular morbidity and mortality. Thus, the overall goal of this research program is to determine the integrative sympathoadrenal and local endothelium-dependent contributors to vascular tone during hypoxic stress in older healthy subjects and older moderate OSA patients. Our general working hypothesis is that there is an alteration in the balance of sympathoadrenal and endothelium-dependent control of vascular tone which leads to a severely impaired peripheral vasodilatory response in older humans, and that this impairment is even greater in older OSA patients. To test our hypothesis we will address the following specific aims: (1) we will determine the sympathoadrenal and peripheral vascular responses to graded systemic hypoxia in older healthy adults and older moderate OSA patients;(2) we will determine whether local blockade of -adrenergic vasoconstriction and -adrenergic mediated vasodilation reduces the age- and disease-group differences in peripheral vascular responses to graded systemic hypoxia;(3) we will determine whether the impaired peripheral vasodilator responses to systemic hypoxia is due to age- and disease-related reductions in the local contribution of endothelium-derived nitric oxide and prostaglandins to this response, and whether acute improvements in endothelium-dependent vasodilation via ascorbic acid infusion augments local hypoxia- induced vasodilation in older healthy and older OSA humans;and (4) we will determine whether augmented endothelin-1 mediated vasoconstriction limits hypoxic vasodilation in older healthy adults and further limits this response in older OSA patients. The methods employed to address these aims are state-of-the-art and involve direct recordings of sympathetic neural activity and local (intra-arterial) administration of various study drugs to determine the mechanisms underlying this age- and disease-related impairment. The findings from the proposed studies will provide novel insight into the integrative control of peripheral vascular tone during hypoxia in older healthy and diseased adults and could have significant clinical implications for understanding vascular function in related patient populations (e.g., congestive heart failure, ischemic vascular disease).
Older healthy adults and patients with obstructive sleep apnea are at elevated risk for the development of cardiovascular disease. The studies in this application are designed to understand how impairments in the control of blood vessel function might contribute to a reduced ability of older healthy adults and sleep apnea patients to respond to conditions in which not enough blood and oxygen are being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older healthy and diseased adults.
|Richards, Jennifer C; Luckasen, Gary J; Larson, Dennis G et al. (2014) Role of ?-adrenergic vasoconstriction in regulating skeletal muscle blood flow and vascular conductance during forearm exercise in ageing humans. J Physiol 592:4775-88|
|Kirby, Brett S; Crecelius, Anne R; Richards, Jennifer C et al. (2013) Sources of intravascular ATP during exercise in humans: critical role for skeletal muscle perfusion. Exp Physiol 98:988-98|
|Crecelius, Anne R; Richards, Jennifer C; Luckasen, Gary J et al. (2013) Reactive hyperemia occurs via activation of inwardly rectifying potassium channels and Na+/K+-ATPase in humans. Circ Res 113:1023-32|
|Kirby, Brett S; Bruhl, Allison; Sullivan, Michelle N et al. (2013) Robust internal elastic lamina fenestration in skeletal muscle arteries. PLoS One 8:e54849|
|Markwald, Rachel R; Kirby, Brett S; Crecelius, Anne R et al. (2011) Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans. J Physiol 589:1979-90|
|Crecelius, Anne R; Kirby, Brett S; Voyles, Wyatt F et al. (2011) Augmented skeletal muscle hyperaemia during hypoxic exercise in humans is blunted by combined inhibition of nitric oxide and vasodilating prostaglandins. J Physiol 589:3671-83|