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Impaired skeletal muscle blood flow control with advancing age in humans: attenuated ATP release and local vasodilation during erythrocyte deoxygenation.

ABSTRACT: Skeletal muscle blood flow is coupled with the oxygenation state of hemoglobin in young adults, whereby the erythrocyte functions as an oxygen sensor and releases ATP during deoxygenation to evoke vasodilation. Whether this function is impaired in humans of advanced age is unknown.To test the hypothesis that older adults demonstrate impaired muscle blood flow and lower intravascular ATP during conditions of erythrocyte deoxygenation.We showed impaired forearm blood flow responses during 2 conditions of erythrocyte deoxygenation (systemic hypoxia and graded handgrip exercise) with age, which was caused by reduced local vasodilation. In young adults, both hypoxia and exercise significantly increased venous [ATP] and ATP effluent (forearm blood flow×[ATP]) draining the skeletal muscle. In contrast, hypoxia and exercise did not increase venous [ATP] in older adults, and both venous [ATP] and ATP effluent were substantially reduced compared with young people despite similar levels of deoxygenation. Next, we demonstrated that this could not be explained by augmented extracellular ATP hydrolysis in whole blood with age. Finally, we found that deoxygenation-mediated ATP release from isolated erythrocytes was essentially nonexistent in older adults.Skeletal muscle blood flow during conditions of erythrocyte deoxygenation was markedly reduced in aging humans, and reductions in plasma ATP and erythrocyte-mediated ATP release may be a novel mechanism underlying impaired vasodilation and oxygen delivery during hypoxemia with advancing age. Because aging is associated with elevated risk for ischemic cardiovascular disease and exercise intolerance, interventions that target erythrocyte-mediated ATP release may offer therapeutic potential.

SUBMITTER: Kirby BS

PROVIDER: S-EPMC3393524 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Impaired skeletal muscle blood flow control with advancing age in humans: attenuated ATP release and local vasodilation during erythrocyte deoxygenation.

Kirby Brett S BS Crecelius Anne R AR Voyles Wyatt F WF Dinenno Frank A FA

Circulation research 20120529 2

<h4>Rationale</h4>Skeletal muscle blood flow is coupled with the oxygenation state of hemoglobin in young adults, whereby the erythrocyte functions as an oxygen sensor and releases ATP during deoxygenation to evoke vasodilation. Whether this function is impaired in humans of advanced age is unknown.<h4>Objective</h4>To test the hypothesis that older adults demonstrate impaired muscle blood flow and lower intravascular ATP during conditions of erythrocyte deoxygenation.<h4>Methods and results</h4 ...[more]

PMID: 22647875

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Project description:Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension.

Dataset Information

Impaired skeletal muscle blood flow control with advancing age in humans: attenuated ATP release and local vasodilation during erythrocyte deoxygenation.

Publications

Impaired skeletal muscle blood flow control with advancing age in humans: attenuated ATP release and local vasodilation during erythrocyte deoxygenation.

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