Not a fine wine: the ATP hypothesis may not get better with age

The regulation of skeletal muscle blood flow during dynamic exercise involves the interaction of local metabolic and systemic neural signals which serve to match oxygen supply with demand. Sympathetic vasoconstriction is required during whole body dynamic exercise to assure maintenance of mean arterial pressure, given that skeletal muscle vasodilator capacity exceeds the potential of humans to increase cardiac output (Rowell et al. 1996). However, sympathetic vasoconstriction is limited in active muscle by local, presumably metabolic, factors in an intensity-dependent manner. This phenomenon was initially termed ‘functional sympatholysis’ but is now understood to encompass a blunting of vasoconstrictor transduction rather than an outright ‘lysis’ of sympathetic outflow to muscle (Hansen et al. 2000). Healthy ageing is associated with a reduced skeletal muscle blood flow response to exercise, particularly at moderate to high intensities. This attenuation results from a combination of reduced metabolic vasodilatation and increased sympathetic vasoconstriction due, in part, to increased adrenergic responsiveness and a reduction in the magnitude of functional sympatholysis (Proctor & Parker, 2006). Reduced functional sympatholysis during exercise has been demonstrated via both reflex (i.e. cold pressor test) and local pharmacological activation of α1- and α2-adrenoceptors, thus suggesting altered postjunctional modulation of adrenergic vasoconstriction with ageing (Dinenno & Joyner, 2006). The peripheral mechanism(s) underlying the relative maintenance of postjunctional adrenergic responsiveness during exercise in ageing, however, remain unclear. Several putative vasodilator substances (adenosine, nitric oxide, prostaglandins) have been examined as contributors to functional sympatholysis in active skeletal muscle; however, these factor(s) have failed to recapitulate the sympatholytic effects of exercise in humans (Tschakovsky et al. 2002; Dinenno & Joyner, 2004). Recent work has identified adenosine triphosphate (ATP) as an attractive sympatholytic candidate in young healthy subjects given its local release from several potential sources in response to muscle contraction and its capacity to induce vasodilatation directly or by limiting adrenergic vasoconstriction. Indeed, ATP accumulates in the interstitium and venous drainage of active skeletal muscle and is capable of abolishing postjunctional α-adrenoceptor-mediated vasoconstriction in the human arm and leg circulations in a dose-dependent manner (Gonzalez-Alonso et al. 2002; Rosenmeier et al. 2004; Kirby et al. 2008; Mortensen et al. 2009). The uniqueness of ATP in this context is highlighted by the failure of its degradation products, ADP, AMP or adenosine, to blunt vasoconstriction to endogenous noradrenaline (norepinephrine; via tyramine infusion) thus inferring activation of P2Y2 receptors as a potential mechanism in young subjects (Rosenmeier et al. 2008). However, the degree to which ATP-mediated sympatholysis is altered by ageing and accounts for deficits in the modulation of adrenergic vasoconstriction during exercise is poorly understood. In this issue of The Journal of Physiology, Kirby et al. (2011) examined this question and report the key observation that, in spite of an ageing-induced deficit of functional sympatholysis during moderate handgrip exercise, ATP-mediated sympatholysis is maintained with age. That is, intra-brachial artery infusion of ATP abolished nearly all postjunctional α1- and α2-adrenoceptor-mediated forearm vasoconstriction in aged subjects. When compared to data from young subjects previously published by the same group, no differences in the magnitude of ATP-mediated sympatholysis between young and aged subjects were apparent. This finding parallels recent results from this group showing the maintenance of ATP-mediated, dose-dependent forearm vasodilatation in aged subjects (Kirby et al. 2010). Taken together, these results demonstrate disparate effects of ageing on exercise-mediated versus ATP-mediated vascular responses, thus adding an interesting wrinkle to the case being made for ATP as an important regulator of skeletal muscle blood flow during dynamic exercise. If ATP is responsible for functional sympatholysis during exercise, as recently suggested (Kirby et al. 2008; Rosenmeier et al. 2008), then why is exercise-mediated sympatholysis reduced with ageing while ATP-mediated sympatholysis is maintained? One possibility is that ATP release is reduced with ageing such that lower [ATP] is present in the circulation of the exercising muscle. In this regard, future studies in this area must address whether ageing influences the release of ATP in the skeletal muscle circulation during exercise. This will be challenging work inasmuch as the measurement of ATP in plasma is confounded by its rapid enzymatic degradation and its release from red blood cells and other formed elements (Gorman et al. 2007). However, a promising development in this area is the recent work of Mortensen et al. (2011), in which intravascular microdialysis was used to sample fluid free of these elements from the venous and arterial circulations of the leg at rest and during graded knee-extensor exercise. These authors showed that stable [ATP] could be obtained from intravascular samples devoid of enzymes and blood-formed elements, a finding that will probably set the standard for future studies of plasma [ATP] in humans at rest and during exercise. Future studies in this area must also address the role of ATP in skeletal muscle blood flow regulation during whole body dynamic exercise of moderate to high intensity, a setting that contrasts small muscle mass (e.g. forearm) exercise due to increases in muscle sympathetic outflow. The role of ATP becomes substantially more complex during sympathetic activation as it is released as a cotransmitter and acts on postjunctional P2X and prejunctional P2 receptors, inducing vasoconstriction and modulating neurotransmitter release (Erlinge & Burnstock, 2008). Nevertheless, the study by Kirby et al. (2011) takes us one step closer to understanding the intricacies of purinergic regulation of skeletal muscle blood flow during exercise and how ageing may (or may not) impact this dynamic system.