Hypertension. 2009 Jun;53(6):993-9.
Adenosine contributes to blood flow regulation in the exercising human leg by increasing prostaglandin and nitric oxide formation.
Mortensen SP, Nyberg M, Thaning P, Saltin B, Hellsten Y.
Source
Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen Ø, Denmark. stefan@sport.dk
Abstract
Adenosine can induce vasodilation in skeletal muscle, but to what extent adenosine exerts its effect via formation of other vasodilators and whether there is redundancy between adenosine and other vasodilators remain unclear. We tested the hypothesis that adenosine, prostaglandins, and NO act in synergy to regulate skeletal muscle hyperemia by determining the following: (1) the effect of adenosine receptor blockade on skeletal muscle exercise hyperemia with and without simultaneous inhibition of prostaglandins (indomethacin; 0.8 to 1.8 mg/min) and NO (N(G)-mono-methyl-l-arginine; 29 to 52 mg/min); (2) whether adenosine-induced vasodilation is mediated via formation of prostaglandins and/or NO; and (3) the femoral arterial and venous plasma adenosine concentrations during leg exercise with the microdialysis technique in a total of 24 healthy, male subjects. Inhibition of adenosine receptors (theophylline; 399+/-9 mg, mean +/- SEM) or combined inhibition of prostaglandins and NO formation inhibited the exercise-induced increase in leg blood flow by 14+/-1% and 29+/-2% (P<0.05), respectively, but combined inhibition of prostaglandins, NO, and adenosine receptors did not result in an additive reduction of leg blood flow (31+/-5%). Femoral arterial infusion of adenosine increased leg blood flow from approximately 0.3 to approximately 2.5 L/min. Inhibition of prostaglandins or NO, or prostaglandins and NO combined, inhibited the adenosine-induced increase in leg blood flow by 51+/-3%, 39+/-8%, and 66+/-8%, respectively (P<0.05). Arterial and venous plasma adenosine concentrations were similar at rest and during exercise.
These results suggest that adenosine contributes to the regulation of skeletal muscle blood flow by stimulating prostaglandin and NO synthesis.
PMID:19433775[PubMed – indexed for MEDLINE]

J Int Soc Sports Nutr. 2012 Oct 9;9(1):48.
Adenosine-5′-triphosphate (ATP) supplementation improves low peak muscle torque and torque fatigue during repeated high intensity exercise sets.
Rathmacher JA, Fuller JC Jr, Baier SM, Abumrad NN, Angus HF, Sharp RL.
Source
Department of Animal Science, Iowa State University, Ames, IA, 50010, USA. Rathmacher@mti-hmb.com.
Abstract
BACKGROUND:
Intracellular concentrations of adenosine-5′-triphosphate (ATP) are many times greater than extracellular concentrations (1-10 mM versus 10-100 nM, respectively) and cellular release of ATP is tightly controlled. Transient rises in extracellular ATP and its metabolite adenosine have important signaling roles; and acting through purinergic receptors, can increase blood flow and oxygenation of tissues; and act as neurotransmitters. Increased blood flow not only increases substrate availability but may also aid in recovery through removal of metabolic waste products allowing muscles to accomplish more work with less fatigue.
The objective of the present study was to determine if supplemental ATP would improve muscle torque, power, work, or fatigue during repeated bouts of high intensity resistance exercise.
METHODS:
Sixteen participants (8 male and 8 female; ages: 21-34 years) were enrolled in a double-blinded, placebo-controlled study using a crossover design. The participants received either supplemental ATP (400 mg/d divided into 2 daily doses) or placebo for 15 d. After an overnight fast, participants underwent strength and fatigue testing, consisting of 3 sets of 50 maximal knee extensions performed on a Biodex® leg dynamometer.
RESULTS:
No differences were detected in high peak torque, power, or total work with ATP supplementation; however, low peak torque in set 2 was significantly improved (p < 0.01). Additionally, in set 3, a trend was detected for less torque fatigue with ATP supplementation (p < 0.10).
CONCLUSIONS:
Supplementation with 400 mg ATP/d for 15 days tended to reduce muscle fatigue and improved a participant’s ability to maintain a higher force output at the end of an exhaustive exercise bout.
PMID:23046855[PubMed] PMCID:PMC3483284

J Physiol. 2008 Oct 15;586(Pt 20):4993-5002.
Activation of ATP/UTP-selective receptors increases blood flow and blunts sympathetic vasoconstriction in human skeletal muscle.
Rosenmeier JB, Yegutkin GG, González-Alonso J.
Source
Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen Ø, Denmark. jaya@dadlnet.dk
Abstract
Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscle in humans, presumably due to the action of vasoactive metabolites (functional sympatholysis). Recently, we demonstrated that infusion of ATP into the arterial circulation of the resting human leg increases blood flow and concomitantly blunts alpha-adrenergic vasoconstriction in a similar manner to that during moderate exercise. Here we tested the hypothesis that ATP, rather than its dephosphorylated metabolites, induces vasodilatation and sympatholysis in resting skeletal muscle via activation of ATP/UTP-selective receptors. To this aim, we first measured leg blood flow (LBF), mean arterial pressure (MAP), cardiac output , leg arterial-venous (a-v) O(2) difference, plasma ATP and soluble nucleotidase activities during intrafemoral artery infusion of adenosine, AMP, ADP, ATP or UTP in nine healthy males. Comparison of the doses of nucleotides and adenosine required for a similar increase in LBF from approximately 0.5 l min(-1) at baseline to approximately 3.5 l min(-1) (without altering MAP but increasing Q significantly) revealed the following rank order of vasoactive potency: ATP (100) = UTP (100) >> adenosine (5.8) > ADP (2.7) > AMP (1.7). The infusions did not cause any shifts in plasma ATP level or soluble serum nucleotidase activities. Combined infusion of the vasodilatory compounds and the sympathetic vasoconstrictor drug tyramine increased plasma noradrenaline in all hyperaemic conditions, but only caused leg and systemic vasoconstriction and augmented O(2) extraction during adenosine, AMP and ADP infusion (LBF from 3.2 +/- 0.3 to 1.8 +/- 0.2 l min(-1); 3.7 +/- 0.4 to 1.7 +/- 0.2 l min(-1) and 3.3 +/- 0.4 to 2.4 +/- 0.3 l min(-1), respectively, P < 0.05). These findings in humans suggest that the vasodilatory and sympatholytic effects of exogenous ATP in the skeletal muscle vasculature are largely mediated via ATP itself rather than its dephosphorylated metabolites, most likely via binding to endothelial ATP/UTP-selective P2Y(2) receptors.
These data are consistent with a role of ATP in skeletal muscle hyperaemia in conditions of increased sympathetic nerve drive such as exercise or hypoxia.
Comment in
Tripartite function of ATP in vascular signalling. [J Physiol. 2008]
Tripartite function of ATP in vascular signalling.Clifford PS. J Physiol. 2008 Oct 15; 586(Pt 20):4783-4. PMID:18703581[PubMed – indexed for MEDLINE] PMCID:PMC2614056

Pharmacol Rep. 2012;64(3):706-13.
Involvement of NMDA receptors in the antidepressant-like action of adenosine.
Kaster MP, Machado DG, Santos AR, Rodrigues AL.
Source
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil. manu.kaster@gmail.com
Abstract
BACKGROUND AND METHOD:
In this work, the contribution of NMDA receptors to the antidepressant-like effect of adenosine in the forced swimming test (FST) was investigated.
RESULTS:
The pretreatment of mice with NMDA or D-serine was able to prevent the anti-immobility effect of either adenosine or MK-801 in the FST. In addition, the administration of a sub-effective dose of adenosine produced a synergistic effect with sub-effective doses of MK-801, ketamine and zinc chloride. Moreover, the immobility time of the mice treated with active doses of adenosine or N(6)-cyclohexyladenosine (CHA) plus MK-801 was not significantly different from that obtained with adenosine, CHA and MK-801 alone; by contrast, the combination between active doses of adenosine and CHA plus an active dose of the tricyclic antidepressant imipramine produced a greater effect in the FST than the administration of either drug alone.
CONCLUSION:
Together, the results suggest that the effect of adenosine in the FST is likely dependent on the inhibition of NMDA receptors mediated by the activation of adenosine A(1) receptors.
PMID:22814023[PubMed – indexed for MEDLINE]

J Physiol. 2012 Oct 15;590(Pt 20):5001-13.
ATP as a mediator of erythrocyte-dependent regulation of skeletal muscle blood flow and oxygen delivery in humans.
González-Alonso J.
Source
Centre for Sports Medicine and Human Performance, Brunel University, Uxbridge, Middlesex UB8 3PH, UK. j.gonzalez-alonso@brunel.ac.uk
Abstract
In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation.
This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g(-1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise.
Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle.
PMID:22711955[PubMed – indexed for MEDLINE] PMCID:PMC3497559

Exerc Sport Sci Rev. 2011 Apr;39(2):102-8.
The role of adenosine monophosphate kinase in remodeling white adipose tissue metabolism.
Gaidhu MP, Ceddia RB.
Source
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Abstract
Recent evidence indicates that the enzyme adenosine monophosphate (AMP) kinase exerts important fat-reducing effects in the adipose tissue, which has created great interest in this enzyme as a potential target for obesity treatment. This review summarizes our findings that chronic AMP kinase activation remodels adipocyte glucose and lipid metabolism and enhances the ability of adipose tissue to dissipate energy within itself and reduce adiposity.
PMID:21206283[PubMed – indexed for MEDLINE]