The roles of adenosine and related substances in exercise hyperaemia

Abstract

The role of adenosine in exercise hyperaemia has been controversial. Accumulating evidence now demonstrates that adenosine is released into the venous efflux of exercising muscle and that adenosine is responsible for 20-40% of the maintained phase of the muscle vasodilatation that accompanies submaximal and maximal contractions. This adenosine is mainly generated from AMP that is released from the skeletal muscle fibres and dephosphorylated by ecto 5'nucleotidase bound to the sarcolemma. During exercise, the concentration of ecto 5'nucleotidase may be increased by translocation from the cytosol, while release of AMP and affinity of ecto 5'nucleotidase for AMP are increased by acidosis. The adenosine so formed, acts on extraluminal A(2A) receptors on the vascular smooth muscle. In addition, ATP is released from red blood cells into the plasma during exercise, in association with the unloading of O(2) from haemoglobin, while ATP and adenosine may be released from endothelium as a consequence of local hypoxia. It is unlikely that this intraluminal ATP, or adenosine, contributes significantly to exercise hyperaemia, for muscle vasodilatation induced by intraluminal ATP or adenosine is strongly nitric oxide dependent, while vasodilatation induced by adenosine in hypoxia is mediated by A(1) receptors. Neither is a recognized feature of exercise hyperaemia.

Figure 1

Comparison between time course of the venous-arterial differences in plasma adenosine concentration and the force frequency of contractions (above) and the change in arterial perfusion pressure (below), during and after contractions of the constant-flow perfused gracilis muscle for 20 min In the graph below, the proportion of the total vasodilatation that could be attributed to the released adenosine, is shown by the stippled area. All recorded data are shown as mean ±s.e.m. Reproduced from Ballard et al. (1987) with permission from Blackwell Publishing Ltd.

Figure 2

Measurements made at rest and during graded dynamic knee extensor exercise A, concentration of adenosine; B, concentrations of ATP, ADP and AMP in human skeletal muscle interstitial fluid, measured in the dialysate; C, femoral arterial blood flow. Data are mean ±s.e.m., n = 5–7 in each case. *Significant increases in adenosine, ATP and blood flow, other symbols indicate significant increases in AMP or ADP: P < 0.05 in each case. Reproduced from Hellsten et al. (1998) with permission from Lippincott, Williams & Wilkins.

Figure 3

Schematic showing potential sources of adenosine and adenine nucleotides in skeletal muscle during exercise Adenine nucleotides and adenosine might be released as such into interstitial fluid from skeletal muscle fibres, or formed after metabolism by ecto-phosphatases or ecto 5′nucleotidase (5′N). ATP may be released from motor and sympathetic neurons during their activation. ATP released from RBCs into plasma and ATP and adenosine released as such from endothelium, or generated by ectoenzymes, may diffuse into interstitial fluid. For further discussion see text.

Figure 5

Effects of NO synthase inhibition on conducted vasodilator responses evoked in arterioles of hamster cremaster muscle by intraluminal application of ATP (left) and on vasodilatation evoked in rat hindlimb muscle by intra-arterial infusion of ATP (right) Left, change in arteriolar diameter after intraluminal application of control vehicle (CON) and graded concentrations of ATP alone (A) and after (B) systemic administration of l-NAME. Arteriolar diameters were measured 150 ± 52 μm upstream from the site of application of ATP. All values are shown as mean ±s.e.m.*Significant change in diameter; +significantly different from change induced by next lower concentration, #significant difference between before versus after l-NAME. Reproduced from McCullough et al. (1997) with permission from The American Physiological Society. Right, femoral vascular conductance (femoral blood flow/arterial blood pressure), before (time 0) and during intra-arterial infusion of ATP, before and after systemic administration of l-NAME, and then, after subsequent administration of the adenosine receptor antagonist 8-SPT. All values are shown as mean ±s.e.m.*P < 0.05 before versus after L-NAME, $P < 0.05 after l-NAME versus after 8-SPT. Drawn from data included in Skinner & Marshall (1996).

Figure 4

Adenosine and AMP accumulation in the medium of non-stimulated and electrostimulated primary skeletal muscle cells: effect of NBMPR and AOPCP Muscle cells were incubated with medium alone (control) or in solution containing either NBMPR or AOPCP, or both. This was performed without electrostimulation (A and C, open symbols) or with electrostimulation (B and D, closed symbols). Values are mean ±s.e.m. of 6–17 cell dishes. *Significantly different from control value at same point in time: P < 0.05. †Significantly different from values measured without electrostimulation: P < 0.05. Reproduced from Lynge et al. (2001) with permission from Blackwell Publishing Ltd.

Figure 6

Effects of the non-selective adenosine receptor antagonist 8-phenyltheophylline (8-PT) and the selective A₁ receptor antagonist ZM 241385 on vasodilatation evoked in cat hindlimb muscle by contraction Graphs show hindlimb vascular conductance calculated as hindlimb blood flow/arterial blood pressure, before (time 0) and during contraction at 3 Hz for 20 min. A, before and after 8-PT; B, before and after ZM241385. In each case, closed symbols show values after antagonist. All values are mean ±s.e.m.*P < 0.05, before versus after antagonist. Reproduced from Poucher (1996) with permission from Blackwell Publishing Ltd.

Figure 7

Change in femoral vascular conductance above baseline Changes shown are for low, medium and high doses of adenosine (Ado) for Ado-responders and non-responders (A) and for low, medium and high exercise workloads for Ado-responders and non-responders (B), before and after infusion of the adenosine receptor antagonist aminophylline (Aph). Values are mean ±s.e.m.*P < 0.05 responders versus non-responders, †P < 0.05 before versus after Aph for responders or non-responders. Reproduced from Martin et al. (2006b) with permission from The American Physiological Society.