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

Regulation of blood flow to contracting skeletal muscle is maintained through a delicate and complex interaction between local vasodilatory and vasoconstricting signals. Large muscle mass exercise increases sympathetic vasoconstrictor signalling through α-adrenoceptors. However, for oxygen delivery to meet metabolic demand, vasoconstriction must be counterbalanced by vasodilatory stimuli. The ability of skeletal muscle vasculature to mitigate sympathetic vasoconstriction during exercise is termed ‘functional sympatholysis’. In young adults, endothelium-dependent vasodilatory signalling contributes to sympatholysis. For example, prior studies report that stimulation of endothelium-dependent vasodilatation through direct, intra-arterial infusion of ATP, alone or during exercise, results in significant attenuation of α1-adrenergic vasoconstriction (Kirby et al. 2008; Hearon et al. 2016). Sympatholysis is impaired in people of advanced age (henceforth referred to as older adults), resulting in exaggerated responsiveness to α-adrenergic stimuli during exercise. Impaired sympatholysis in older adults probably contributes to blood flow disturbances, deficient oxygen delivery, metabolic dysfunction and declines in exercise capacity. Exercise capacity is an independent predictor of all-cause mortality. The mechanisms behind impaired sympatholysis in older adults are not fully understood but probably derive in part from imbalances between local vasoconstrictive and dilatory signals. Indeed, relative to young adults, older adults have elevated muscle sympathetic nervous system activity at rest, and experience increased noradrenaline spillover during whole-body exercise. On the other hand, impaired sympatholysis may also stem from a lack of vasodilatory signalling; older adults have impaired responsiveness to dilatory stimuli (i.e. endothelial dysfunction), as well as reduced production of vasodilatory signals such as plasma ATP during exercise. One implication of these observations is that impaired sympatholysis in older adults may not be a result of intrinsic endothelial defects but rather reduction in endothelium-dependent vasodilatory signal (e.g. plasma ATP). 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 α1-adrenoceptors during handgrip exercises of mild and moderate intensity with and without infusion of an endothelium-dependent vasodilatory signal. For brevity, only a select methodology and results are outlined here; a complete methodology and results are provided in the original article (Hearon et al. 2020). Figure 1A summarizes the experimental design. Forearm vascular conductance (FVC), an index of vascular tone, was derived from ultrasound-based measurements of forearm blood flow (FBF) and catheter-based measurements of mean arterial pressure (FVC = FBF/MAP). FVC was measured in a number of settings. The first was during baseline (no exercise, no infusions). FVC measurement was also obtained during handgrip exercise at 5% maximal voluntary contraction (MVC) effort (mild intensity), at 15% MVC (moderate intensity), at 5% MVC plus intra-arterial (brachial) infusion of ATP and at 15% MVC plus ATP infusion. FVC was also determined after infusion of the selective α1-adrenoceptor agonist phenylephrine (PE) applied during the existing experimental condition, as depicted schematically in Fig. 1A. PE can reduce FVC through activation of α1-adrenergic receptors mimicking sympathetic vasoconstriction. The percent reduction in FVC pre-to-post PE infusion was used as an index of sympatholysis. A relatively small reduction in FVC following PE infusion suggests sympatholysis-mediated attenuation of α1-adrenergic vasoconstriction. Participants included eight men and eight women. Their age averaged 68 years, and they were in good health (no medications, non-smokers, normotensive, etc.). Experiments were completed at the Human Cardiovascular Physiology Laboratory at Colorado State University. As an abbreviated summary of the results, prior studies of young adults had demonstrated increases in FVC between baseline and handgrip exercise at 5% MVC and between baseline and handgrip exercise at 15% MVC (Hearon et al. 2016), consistent with the known hyperaemic effects of these exercises. Infusion of PE overtop of handgrip exercise in these young adults resulted in FVC decreases at both exercise intensities; however, the percentage decrease was mitigated at 15% MVC as a result of functional sympatholysis (Figure 1B) (Hearon et al. 2016). By contrast, the sympatholysis evident in young adults at 15% MVC, was significantly impaired in older adults (Figure 1C), 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 1D) (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 α1-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. Furthermore, these findings demonstrate that, given sufficient stimulus, endothelium-dependent vasodilatation is sufficiently powerful to attenuate α1-adrenergic vasoconstriction even in a setting, such as older adulthood, where this sympathetic signal is exaggerated. Importantly, these findings suggest augmentation of endothelium-dependent vasodilatory stimuli as a potential treatment for impaired sympatholysis in older adults. Erythrocytes represent a potential therapeutic target because they are the primary intravascular source of ATP during exercise. In older adults, plasma ATP concentration during exercise is reduced, and erythrocyte release of ATP during deoxygenation is impaired (Kirby et al. 2012). In vitro evidence indicates that erythrocytes release ATP in response to mechanical deformation, shear stress, and O2 offloading. Thus, the pathways relevant to these mechanisms represent potential therapeutic targets. 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. No competing interests declared. Sole author. This publication was supported by NIH grant T32 HL134643 and the Medical College of Wisconsin Cardiovascular Center's A.O. Smith Fellowship Scholars Program. The author offers sincere thanks to Professor Alison J. Kriegel for mentorship.