Augmentation of endothelium‐dependent vasodilatory signalling improves functional sympatholysis in contracting muscle of older adults

KEY POINTS: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical to maintain blood flow during exercise-mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In this investigation, intra-arterial infusion of ACh or ATP to augment endothelium-dependent signalling during exercise attenuated alpha1 -adrenergic vasoconstriction in contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age-related impairment in functional sympatholysis likely results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. ABSTRACT: The ability of contracting skeletal muscle to attenuate sympathetic alpha-adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults increasing endothelium-dependent vasodilatory signalling during mild exercise augments sympatholysis. Here, we tested the hypothesis that increasing endothelium-dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1 n = 8, Protocol 2 n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of phenylephrine (PE; alpha1 -agonist) during 1) infusion of an endothelium-dependent vasodilator alone (Protocol 1: acetylcholine [ACh] or Protocol 2: low dose adenosine triphosphate [ATP], 2) mild handgrip exercise (5% maximum voluntary contraction; MVC), 3) moderate handgrip exercise (15% MVC), and 4) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium-dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (DeltaFVC: ACh: -31 +/- 3 and ATP: -30 +/- 4%). PE-mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (DeltaFVC: 5% MVC: -30 +/- 9; 15% MVC: -33 +/- 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium-dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE-mediated vasoconstriction (DeltaFVC: -13 +/- 1 and -19 +/- 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that given a sufficient stimulus, endothelium-dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach to improving sympatholysis, and thus tissue blood flow and oxygen delivery in older adults. This article is protected by copyright. All rights reserved.