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During exercise, contraction of the skeletal muscle causes an increase in the demand for oxygen that is compensated for by an increase in blood flow and thus oxygen delivery to the exercising muscle (Gonzalez-Alonso 2008;Kirby et al. 2008;Rosenmeier et al. 2004). This increase in blood flow is determined by the competing influence from metabolites that are released locally within the skeletal muscle to cause vasodilation (Rosenmeier, Hansen, & Gonzalez-Alonso 2004) and increases in muscle sympathetic nerve activity (MSNA; (Clifford 2008). Increased MSNA causes vasoconstriction in the inactive muscle to re-direct blood flow to the exercising muscle where there is a greater demand for oxygen (Joyner and Thomas 2003). However, recently it has been shown that despite an increase in MSNA, sympathetic control in the contracting muscle is reduced or completely abolished (Gonzalez-Alonso 2008;Rosenmeier, Hansen, & Gonzalez-Alonso 2004). It was originally postulated that this 'functional sympatholysis' (Joyner & Thomas 2003;Rosenmeier, Hansen, & Gonzalez-Alonso 2004) is a consequence of increased interstitial and circulating metabolites; namely hydrogen (H+), inorganic phosphate (Pi), potassium (K+), prostaglandins (PGs), adenosine and nitric oxide (NO), that are evident with exercise (Gonzalez-Alonso 2008). More recently however, emerging evidence suggests that adenosine triphosphate (ATP) is the only metabolite that is capable of inducing both skeletal muscle vasodilation and blunting vasoconstriction to regulate skeletal muscle blood flow during exercise (Gonzalez-Alonso 2008).
Although the presence of ATP during exercise is well documented, it is unclear as to where the source of ATP originates. It is known that ATP can be present in high concentrations during muscle contraction but interestingly is unable to cross the endothelium (Clifford 2008). It has been postulated therefore, that in conditions of high oxygen demand erythrocytes function as an oxygen sensor thereby releasing ATP in response to the number oxygen bindings sites that are available in the haemoglobin molecule (Gonzalez-Alonso et al. 2002). Consistent with this possibility, recent investigations have been carried out to determine whether plasma ATP concentration increases in response to dynamic handgrip exercise and whether this increase corresponds to a decrease in venous oxygen content (Wood et al. 2009). Measurements were taken from ten healthy male volunteers at rest and during 30 and 180 s of dynamic handgrip exercise at 45% maximal voluntary contraction (MVC). Results demonstrated an initial increase in venous plasma ATP concentration from baseline to 30 s of handgrip exercise (0.60 ± 0.17 and 1.04 ± 0.33 µM/L, respectively) which remained significantly elevated after 180 s into exercise (0.92 ± 0.26 µM/L; (Wood, Wishart, Walker, Askew, & Stewart 2009). This increase in ATP concentration was inversely correlated to a significant reduction in venous oxygen content (from 102.8 ± 22.5 mL/L at rest to 68.3 ± 16.0 mL/L after 30 s exercise) that remained significantly lower than rest after 180 s of exercise (75.8 ± 14.8 ml/L; (Wood, Wishart, Walker, Askew, & Stewart 2009). Although these results do not provide direct evidence to demonstrate the exact source of ATP, findings are consistent with the assertion that deoxygenation of blood (as is the case during exercise) acts a stimulus for the release of ATP (Wood, Wishart, Walker, Askew, & Stewart 2009). It has been proposed that ATP released in this manner is controlled by the cystic fibrosis transmembrane conductance regulator (Sprague et al. 1998). However, in disagreement to the above findings, previous research has demonstrated that both patients with cystic fibrosis and healthy controls elicit identical blood flow responses to incremental handgrip exercise at 5, 10 and 15% MVC (Schrage et al. 2005). Therefore, it may be reasonable to assume that ATP release originates from the erythrocyte but may be stimulated by an alternative pathway. There is recent evidence to suggest that the release of ATP from red blood cells is stimulated by intracellular cAMP (Sprague et al. 2001).
One of the first studies to investigate the role of ATP in the regulation of skeletal muscle blood flow during exercise was carried out by Rosenmeier et al (2004). Measures of leg blood flow (LBF) and mean arterial pressure (MAP) were obtained during infusion of adenosine (1.25 mg ml-1 at a rate of 16 µmol min-1), ATP (1mg ml-1 at a rate of 1µmol min-1) or during knee-extensor exercise (~20W). Similar measures were then taken during the combined infusion of tyramine (0.52mg ml-1 at a rate of ~13.21µmol min-1); a well known vasoconstrictor drug that acts to cause release of noradrenalin from sympathetic nerve terminals (Rosenmeier, Hansen, & Gonzalez-Alonso 2004). Findings indicated that despite a significant increase in MSNA and venous noradrenalin, tyramine evoked vasoconstriction was completely abolished in response to both ATP infusion and exercise, but not in response to adenosine infusion (LBF decreased from 3.8 ± 0.3 to 1.7 ± 0.21 lmin-1). Therefore, these data suggest that ATP may be implicated in the regulation of blood flow and oxygen delivery by inducing vasodilation which overrides any concurrent increase in sympathetic vasoconstriction (Rosenmeier, Hansen, & Gonzalez-Alonso 2004). It is interesting to note that the apparent increase in vasodilation is evident despite elevated noradrenalin levels and any accumulation of metabolites within the muscle (Gonzalez-Alonso 2008). Thus, this may suggest that the contributory effect of ATP is at the level of the post-junctional Î±-adrenoreceptors that are located on the vascular smooth muscle, but was not directly assessed in this study (Gonzalez-Alonso 2008). To ascertain this possibility Kirby et al (2008) designed an experiment whereby selective Î±-1- and Î±-2-adrenoreceptor agonists were used to elicit vasoconstriction as opposed to tyramine which stimulates these receptors indirectly (Gonzalez-Alonso 2008). Using Doppler ultrasound techniques, measures of forearm blood flow (FBF) were obtained to determine the vasoconstrictor response to direct Î±1- or Î±2 - receptor stimulation (via phenylephrine and dexmedetomidine, respectively) during moderate intensity handgrip exercise (~15 MVC), infusion of adenosine (73 ± 8 nmol (dl forearm volume)-1 min-1) and infusion of ATP (11 ± 2 nmol (dl forearm volume)-1 min-1). Findings demonstrated that both adenosine infusion and handgrip exercise decreased the vasoconstrictor response to direct Î±1- and Î±2-adrenoreceptor stimulation (âˆ† FVC -39 ± 5% and -11 ± 3% respectively), however this response was completely abolished as a result of infusion of ATP (âˆ† FVC = -3 ± 2%). These results contrast those reported by Rosenmeier et al (2004) whereby both exercise and ATP completely abolished the vasoconstrictor response to tyramine but adenosine infusion reportedly had no effect. This discrepancy between findings may be attributed to the difference in exercise that is employed in either study. It has recently been shown that functional sympatholysis is dependent on muscle mass (Gonzalez-Alonso 2008). Thus, it is possible that the greater contraction of muscle mass required for knee extensor exercise (Rosenmeier, Hansen, & Gonzalez-Alonso 2004) caused attenuation of local vasodilator signals i.e. adenosine, whereas contraction of a small muscle mass as required for handgrip exercise may allow local vasodilator factors to dominate. It is therefore difficult to determine whether the sympatholytic effect of ATP is determined by ATP itself, or products of ATP degradation. To further differentiated the effect of adenosine and ATP infusion, additional research was carried out to demonstrate that progressive infusion of ATP significantly reduced the vasoconstrictor response during moderate to high doses whereas the vasoconstrictor response to graded infusion of adenosine was progressively greater (Gonzalez-Alonso 2008). Thus these findings suggests that the sympatholytic effect of ATP acts at the level of the post-junctional Î±1- and Î±2- adrenoreceptors and furthermore that this response is graded dependent of the dose of ATP (Kirby, Voyles, Carlson, & Dinenno 2008). These findings are limited however when considering that little attention has been given as to whether ATP induced sympatholysis is mediated by ATP itself or the products of ATP breakdown, i.e. adenosine diphosphate (ADP) and adenosine monophosphate (AMP) (Gonzalez-Alonso 2008). A study carried out my Rosenmeier et al (2008) conducted an experiment to investigate this possibility and demonstrated that neither ADP, AMP or adenosine infusion abolished the vasoconstrictor response evoked by infusion of tyramine (Gonzalez-Alonso 2008;Rosenmeier et al. 2008) suggesting that it is the distinctive ability of ATP itself, rather than its dephosphorylated metabolites that attenuate the sympathetic vasoconstriction response during exercise (Clifford 2008).
It is thought that ATP exerts its regulatory effect on blood flow via activation of purinergic receptors (Mortensen et al. 2009a;Mortensen, Gonzalez-Alonso, Nielsen, Saltin, & Hellsten 2009b). It has previously been shown that activation of the P2x receptors located in smooth muscle cells will induce vasoconstriction whereas activation of the P2y receptors located on the vascular endothelium induces vasodilation (Burnstock 2007). However, recent analysis of purinergic receptor mRNA by use of immunohistochemistry techniques has shown that P2x1 as well as P2y2 receptors are located on the vascular endothelium; suggesting that both these receptors are involved in the vasodilatory response to ATP in the skeletal muscle (Mortensen, Gonzalez-Alonso, Bune, Saltin, Pilegaard, & Hellsten 2009a). It has been suggested that ATP-induced vasodilation is incurred by triggering the release endothelium-derived relaxing factors (EDRFs) from P2y receptors (Mortensen, Gonzalez-Alonso, Bune, Saltin, Pilegaard, & Hellsten 2009a). To ascertain this possibility Mortensen et al (2009a) investigated whether the vasodilatory response to ATP is mediated by NO or PGs by employing inhibitors of these metabolites in addition to determining as to whether ATP-induced vasodilation is partly mediated by activation of P1 receptors (adenosine receptors). Systemic and leg blood flow were measured in nineteen healthy male participants at rest and during ATP infusion (0.45-2.45 Î¼mol/min) into the femoral artery for 5-7 minutes under either a control condition, NG-monomethyl-L-arginine (L-NMMA; a nitric oxide synthase inhibitor, 12.3 ± 0.3 mg/min) alone, indomethacin (INDO; inhibits production of prostaglandins, 613 ± 12Î¼g/min) alone, combined L-NMMA and INDO or theophylline infusion (TEO; adenosine receptor blocker, 400 ± 26mg). In response to the infusion of ATP, results demonstrate an increase in LBF from baseline (by 1.82 ± 0.14 l/min) that was not present when ATP was co-infused with either L-NMMA or INDO whereby LBF was actually significantly decreased (from 2.45 ± 0.29 after ATP infusion to 1.79 ± 0.17 and 1.83 ± 0.17l/min respectively). Furthermore, there is evidence to show that this reduction in LBF is greatest when the two inhibitors were combined (from 2.45 ± 0.29 to 1.39 ± 0.03l/min) whereas infusion of TEO had no effect on leg hyperaemia or systemic variables. These results therefore suggest that both NO and PGs play a role in ATP-induced vasodilation but blockade of P1 receptors has no effect thereby eliminating a contributory role for adenosine (Mortensen, Gonzalez-Alonso, Bune, Saltin, Pilegaard, & Hellsten 2009a).
Although ATP has been shown to induce both vasodilation and blunt the vasoconstrictor response to exercise, the mechanisms underlying this effect have only recently been considered (Mortensen, Gonzalez-Alonso, Nielsen, Saltin, & Hellsten 2009b). Mortensen et al (2009b) recruited ten healthy male individuals to undergo 15 minutes of both ATP infusion into the femoral artery (0.03 and 0.14 µmol/min-1/kg leg mass-1) and one leg knee extensor exercise (18 ± 0 and 13 ± 1 W) that was interspersed by 45 min of rest (Mortensen, Gonzalez-Alonso, Nielsen, Saltin, & Hellsten 2009b). Simultaneous blood samples (1-5ml) from the femoral artery and vein were taken at rest and during both ATP infusion and exercise trials (1.5, 4 10 min; (Mortensen, Gonzalez-Alonso, Nielsen, Saltin, & Hellsten 2009b). Results indicated that neither adenosine nor interstitial nucleotides changed in response to arterial infusion of ATP whereas the concentration of noradrenalin was increased to a similar level during muscle contraction, ATP infusion and in the control muscle. It is interesting to note, that despite an increase in noradrenalin concentration (suggesting increased MSNA), findings clearly indicate an increase in LBL in response to both intraluminal infusion of ATP and one leg knee extensor exercise (from ~0.3l/min to 4.2 ± 0.3 and 4.6 ± 0.5l /min, respectively). Conclusively, these findings suggest that the sympatholytic and vasodilatory response to intraluminal infusion of ATP is mediated via purinergic receptors located on the vascular endothelium. Additionally, given the vasodilatory response that has been reported despite increased MSNA, findings support the concept that ATP-induced vasodilation overrides any concurrent increase in vasoconstriction.
In conclusion, investigation into the role of ATP in the regulation of skeletal muscle blood flow has clearly demonstrated ATP as a potent substance to induce vasodilation and blunt sympathetic vasoconstrictor response during exercise. However, the mechanisms underlying this functional sympatholysis have only recently been investigated and further research is required to elucidate as to the exact contributory role of EDRFs.