Endothelin-A -Mediated Vasoconstriction During Exercise With Advancing Age

Barrett-O’Keefe, Zachary; Ives, Stephen J.; Trinity, Joel D.; Morgan, Garrett; Rossman, Matthew J.; Donato, Anthony J.; Runnels, Sean; Morgan, David; Gmelch, Benjamin S.; Bledsoe, Amber D.; Richardson, Russell S.; Wray, D. Walter

doi:10.1093/gerona/glu065

Cited by 41 publications

(56 citation statements)

References 48 publications

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“…This attenuation in exercise-induced hyperemia has been attributed to various age-related alterations in the vascular mechanisms that regulate muscle perfusion (5,40). The lower Q L in the old compared with the young participants observed in our experiments supports these earlier observations (Fig.…”

Section: Aging and Exercise-induced Peripheral Hemodynamicssupporting

confidence: 90%

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

Sidhu

Weavil

Venturelli

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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-We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 Ϯ 2 yr) and nine young (YNG; 24 Ϯ 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (Q L), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and Q L ϳ17% in YNG, while the decrease in cardiac output in OLD (ϳ5%) was significantly smaller with no impact on Q L (P ϭ 0.8). Therefore, in the face of similar significant ϳ7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ϳ11% in OLD, but decreased ϳ8% in YNG. The opposing direction of change was reflected in SVC with a significant ϳ5% increase in OLD and a ϳ12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

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Section: Aging and Exercise-induced Peripheral Hemodynamicssupporting

confidence: 90%

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

Sidhu

Weavil

Venturelli

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…When considering that blood flow is determined by the integration of central (cardiac output, mean arterial pressure) and peripheral hemodynamics (vascular conductance or resistance) and the multitude of factors that regulate these processes during exercise, it is unlikely that a single molecule will encompass the properties of a master regulator. Indeed, thus far, this notion is supported by many elegant investigations utilizing pharmacological dissection of specific vasodilatory pathways [6–8, 13–18]. However, when considering the overall goal of increased blood flow during exercise, to match oxygen delivery and oxygen demand, it becomes evident that even minor modifications in blood flow in the intact human may have significant consequences in terms of physical performance [19].…”

Section: Introductionmentioning

confidence: 99%

Regulation of exercise blood flow: Role of free radicals

Trinity

Broxterman

Richardson

2016

Free Radical Biology and Medicine

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During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an “optimal” redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs.

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“…A subset of these data focusing on the role of ET A receptor inhibition and blood flow regulation during basal conditions and knee extension exercise in these study participants has been reported previously [35]. Study participants were not taking any prescription medications and were free of overt cardiovascular disease.…”

Section: Methodsmentioning

confidence: 99%

“…Upon arrival at the laboratory, body mass and height were recorded, and the right femoral artery was catheterized (18-gauge central venous catheter; Arrow International, Reading, Pennsylvania, USA) using the Seldinger technique. After the catheter placement, study participants rested for ~30 min and then performed knee extension exercise as previously described for a separate investigation [35]. After knee extension exercise, study participants rested for at least 60 min to ensure the return to baseline central and peripheral hemodynamics, including LBF, mean arterial pressure (MAP), and heart rate.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that inhibition of the ET A receptor abolished the age-related reduction in leg blood flow (LBF) in healthy older individuals [35], revealing an important role of endogenous ET-1 in the regulation of the vasculature of the leg. Given this previous finding and the established role of ET-1 in atherosclerosis and endothelial dysfunction, this study sought to determine whether ET-1, acting through the ET A receptor, contributes to the proatherogenic shear rate pattern in the legs of older adults.…”

Section: Introductionmentioning

confidence: 99%

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Endogenous endothelin-1 and femoral artery shear rate

Trinity¹,

Barrett-O’Keefe²,

Ives

et al. 2016

Journal of Hypertension

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Background Both altered shear rate and endothelin-1 (ET-1) are associated with the age-related development of atherosclerosis. However, the role of ET-1, a potent endogenous vasoconstrictor, in altering shear rate in humans, especially in the atherosclerotic-prone vasculature of the leg, is unknown. Therefore, this study examined the contribution of ET-1 to the age-related alterations in common femoral artery (CFA) shear rate. Method BQ-123, a specific endothelin type A (ETA) receptor antagonist, was infused into the CFA, and diameter and blood velocity were measured by Doppler ultrasound in young (n = 8, 24 ± 2 years) and old (n = 9, 70 ± 2 years) study participants. Results and conclusion The old had greater intima–media thickening in the CFA, indicative of a preatherogenic phenotype. Prior to infusion, the old study participants exhibited reduced mean shear rate (27 ± 3/s) compared with the young study participants (62 ± 9/s). This difference was likely driven by attenuated antegrade shear rate in the old as retrograde shear rate was similar in the young and old. Inhibition of ETA receptors, by BQ-123, increased leg blood flow in the old, but not in the young, abolishing age-related differences. Older study participants had a larger CFA (young: 0.82 ± 0.03 cm, old: 0.99 ± 0.03 cm) in which BQ-123 induced significant vasodilation (5.1 ± 1.0%), but had no such effect in the young (−0.8 ± 0.8%). Interestingly, despite the age-specific, BQ-123-induced increase in leg blood flow and CFA diameter, shear rate patterns remained largely unchanged. Therefore, ET-1, acting through the ETA receptors, exerts a powerful age-specific vasoconstriction. However, removal of this vasoconstrictor stimulus does not augment mean shear rate in the old.

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Endothelin-A -Mediated Vasoconstriction During Exercise With Advancing Age

Cited by 41 publications

References 48 publications

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

Regulation of exercise blood flow: Role of free radicals

Endogenous endothelin-1 and femoral artery shear rate

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