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PERSPECTIVES |
1 Department of Medicine, Division of Clinical Pharmacology, and the Autonomic Dysfunction Center, Vanderbilt University School of Medicine, Nashville, TN 37232-2195, USA
Email: italo.biaggioni{at}vanderbilt.edu
Exercise induces a number of adaptive changes that ensure adequate blood supply to the exercising muscles while maintaining systemic homeostasis. Sustained static exercise triggers sympathetic activation and increases in heart rate and blood pressure. This exercise pressor reflex (EPR) and the metabolites that trigger it are the focus of this Perspective.
Among the processes that contribute to the EPR are cortical impulses that initiate voluntary muscle contraction (central command), activation of mechanosensitive afferent fibres (mostly type III fibres) by the contracting muscle, and activation of chemosensitive afferent fibres (mostly type IV fibres) by metabolites generated from the mismatch between energy demand and supply. The identification of the metabolite(s) responsible for the activation of chemosensitive afferent fibres has been an area of great interest and some controversy. Potential candidates should meet the following criteria: (1) their interstitial concentrations increase during exercise; (2) their exogenous application triggers sympathetic and cardiovascular changes that mimic the EPR; and (3) their elimination or blockade blunts the EPR.
Adenosine, known to activate a variety of afferent fibres triggering sympathetic activation (e.g. arterial chemoreceptors, renal and myocardial afferents), has been proposed as a metabolic trigger of the EPR. In support of this hypothesis, interstitial concentrations of adenosine increase during ischaemic exercise in humans (even after accounting for the local trauma invariably associated with the microdialysis technique used) and correlate with the magnitude of sympathetic activation; adenosine is not a potent stimulus of chemosensitive afferents in the anaesthetized cat model (Kaufman & Hayes, 2002), but in humans local administration of adenosine into the forearm triggers sympathetic activation not explained by spillover into the systemic circulation and abolished if afferent nerve traffic is interrupted by axillary blockade, and the adenosine receptor antagonist theophylline blunts the EPR (Biaggioni, 2003). Against this hypothesis, potentiation of endogenous adenosine with the nucleoside uptake blocker dipyridamole failed to enhance the increase in blood pressure induced by intermittent isometric handgrip (Riksen et al. 2005). These investigators, however, did not use postcirculatory ischaemia, the preferable paradigm to selectively investigate the contribution of metaboreceptors to the EPR, nor did they measured sympathetic activation directly. Nonetheless, it is fair to say that the adenosine hypothesis requires further validation, ideally using selective adenosine antagonists currently under development.
In this issue of The Journal of Physiology, Kindig et al. (2007) propose ATP as a metabolic trigger of the EPR. Evidence from previous studies, cited in their paper, favours this hypothesis: ATP concentrations increase linearly with muscle contraction; ATP agonists stimulate group IV chemosensitive fibres in animals, an effect blocked by the purported P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-di-sulphonate (PPADS); and PPADS blocks the EPR in animal models. In their current study, the authors found that PPADS prevents the stimulation of type IV chemosensitive afferents induced by static exercise. Thus, ATP appears to meet all the requirements of a metabolic trigger of the EPR. Only time will tell whether contradictory reports will be forthcoming as has been the case with other candidates. It should be noted that PPADS may have actions unrelated to purine receptors such as blocking arachidonic acid release (Shehnaz et al. 2000). It would be reassuring if these results are confirmed with other P2 antagonists in animal models, and we look forward to human studies using selective P2 receptor antagonists, when and if they become available.
The metabolite signalling a mismatch between energy consumption and oxygen supply in exercising muscle would ideally not only trigger the EPR but also mediate local vasodilatation to increase blood flow to the exercising muscle. It is unclear if ATP fulfills this profile because it induces vasodilatation in some vascular beds, most often via release of NO, EDHF or prostacyclin, and direct vasoconstriction in others, including the hindlimb vasculature as acknowledged by the authors. Nonetheless, purinergic mechanisms combining ATP and adenosine could provide the ideal interaction between metabolic and autonomic factors that regulate cardiovascular function during static exercise (Fig. 1): (1) ATP and adenosine increase when metabolic demands exceed energy supply, and activate P2 and P1 receptors, respectively; (2) ATP (and adenosine?) then activates chemosensitive fibres that contribute to the EPR; (3) the resultant sympathetic activation leads to systemic vasoconstriction, increased blood pressure and improved perfusion pressure; and (4) locally, metabolic vasodilatation and ‘functional sympatholysis’ protect the exercising muscle from systemic vasoconstriction, and adenosine can contribute to both actions. ATP is coreleased with noradrenaline upon sympathetic stimulation and is converted in the synapse to adenosine, which can then activate presynaptic P1 receptors inhibiting further release of noradrenaline.
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References
Biaggioni I (2003). Clin Auton Res 13, 7–9.[CrossRef][Medline]
Kaufman MP & Hayes SG (2002). Clin Auton Res 12, 429–439.[CrossRef][Medline]
Kindig AE, Hayes SG & Kaufman MP (2007). J Physiol 578, 301–308.
Riksen NP, van Ginneken EE, van den Broek PH, Smits P & Rongen GA (2005). J Appl Physiol 99, 522–527.
Shehnaz D, Torres B, Balboa MA & Insel PA (2000). J Pharmacol Exp Ther 292, 346–350.
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