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

Abstract

Key points The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining 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 the present study, intra‐arterial infusion of ACh or ATP to augment endothelium‐dependent signalling during exercise attenuated α1‐adrenergic vasoconstriction in the 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 probably 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 α‐adrenergic vasoconstriction (‘functional sympatholysis’) is impaired with age. In young adults, increasing endothelium‐dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, 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; α1‐agonist) during (i) infusion of an endothelium‐dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) 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 (ΔFVC: ACh: −31 ± 3 and ATP: −30 ± 4%). PE‐mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 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 (ΔFVC: −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 for improving sympatholysis and thus tissue blood flow and oxygen delivery in older adults.

Rescue of impaired sympatholysis in older adults by exogenous administration of endothelium‐dependent vasodilatory signal

“…By contrast, the sympatholysis evident in young adults at 15% MVC, was significantly impaired in older adults (Figure 1), as prospectively observed and documented by Hearon et al . (2020), and also consistent with prior published data (Kirby et al . 2011).…”

“…However, in older adults, intra‐arterial infusion of ATP during 15% MVC restored sympatholysis (Figure 1) (Hearon et al . 2020). Collectively, these observations indicate that impairment of sympatholysis in older adults can be restored, at least partially, by increasing the signal (ATP) required for endothelium‐dependent vasodilatation.…”

“…The central finding of the study by Hearon et al . (2020) is that sympatholysis achieved through endothelium‐dependent vasodilatation can overcome α 1 ‐adrenergic vasoconstriction in older adults given sufficient stimulus. This finding implies that the endothelial machinery required to cause sympatholysis in response to specific vasodilatory stimuli, such as ATP, is functional in older adults.…”

“…For example, the Hearon et al . (2020) suggested rho‐kinase inhibition as a possible means by which to increase ATP release during erythrocyte deoxygenation. The strengths of their study included a well‐controlled subject population and experimental methodology, which together enabled clear interpretation of the results and revealed an important finding.…”

“…Based upon these observations, in a recent article in The Journal of Physiology , Hearon et al . (2020) hypothesized that the endothelium of older adults is capable of attenuating α‐adrenergic vasoconstriction during muscle contractions if provided with sufficient endothelium‐dependent vasodilatory stimulus. They tested their hypothesis in healthy older adults by directly stimulating α 1 ‐adrenoceptors during handgrip exercises of mild and moderate intensity with and without infusion of an endothelium‐dependent vasodilatory signal.…”