From the Copenhagen Muscle Research Centre, August Krogh Institute, and
Rigshospitalet, University of Copenhagen, Denmark.
Correspondence to Ylva Hellsten, Copenhagen Muscle Research Centre, August Krogh Institute, Universitetsparken 13, DK-2100 Copenhagen Ø, Denmark. E-mail ylva.hellsten{at}pop.aki.ku.dk
Methods and Results—The interstitial
adenosine concentration was determined in the vastus lateralis
muscle of healthy humans via dialysis probes inserted in the muscle.
The probes were perfused with buffer, and the dialysate samples were
collected at rest and during graded knee extensor exercise. At rest,
the interstitial concentration of adenosine was
220±100 nmol/L and femoral arterial blood flow (FaBF) was
0.19±0.02 L/min. When the subjects exercised lightly, at a work rate
of 10 W, there was a markedly higher (1140±540 nmol/L;
P<0.05) interstitial adenosine
concentration and a higher FaBF (2.22±0.18 L/min;
P<0.05) compared with at rest. When exercise was
performed at 20, 30, 40, or 50 W, the concentration of
adenosine was moderately greater for each increment, as was the
level of leg blood flow. The interstitial concentrations of
ATP, ADP, and AMP increased from rest (0.13±0.03, 0.07±0.03, and
0.07±0.02 µmol/L, respectively) to exercise (10 W; 2.00±1.32,
2.08±1.23, and 1.65±0.50 µmol/L, respectively;
P<0.05).
Conclusions—The present study provides, for the first time,
interstitial adenosine concentrations in human
skeletal muscle and demonstrates that adenosine and its
precursors increase in the exercising muscle interstitium, at a rate
associated with intensity of muscle contraction and the magnitude of
muscle blood flow.
Microdialysis Technique
Leg Blood Flow
Analysis
Statistics
The muscle interstitial concentrations of ATP, ADP, and AMP
at rest were 126±30, 73±30, and 67±20 nmol/L, respectively. The
concentrations of adenine nucleotides were higher
(P<0.05) at 10 W than at rest, and the
nucleotide levels were moderately elevated with the
increases in work rate (Figure
Leg blood flow at rest was 0.19±0.02 L/min and was elevated
(P<0.05) for each increment in work rate (Figure
Exercise had a marked effect on the muscle interstitial
adenosine concentrations with an
It should be mentioned that nucleotides could have been
released from cells because of tissue damage induced by the insertion
of the microdialysis probes into the muscle. Nevertheless, the 5
exercise intensities were performed in random order, and it appears
unlikely that the change in intracellular adenine
nucleotides and adenosine concentrations would be
gradual if the cause of increase was merely due to damage.
The enzyme responsible for adenosine formation in
skeletal muscle tissue is AMP 5'-nucleotidase. This enzyme exists both
as a soluble cytosolic enzyme and as an ectoenzyme located in the
membrane of cells, with the active site probably facing out toward the
extracellular space.11 12 Although the proportion
of the enzyme existing in an ectoform has not been established in human
skeletal muscle, studies on other animal cell types, such as cardiac
myocytes, suggest that a majority of the enzyme is
membrane-bound.13 With a large proportion of the
enzyme located in the cell membranes of the muscle, the formation of
adenosine would occur in the interstitial space,
provided that the substrate AMP is present. In the present
study, it was found that the concentration of AMP as well as ADP and
ATP increased in the interstitium with exercise. As for
adenosine, the interstitial concentrations of AMP,
ADP, and ATP increased the most from rest to 10 W of exercise. These
findings suggest that the interstitium is a potential site for
adenosine formation. Furthermore, the
Km for AMP for 5'-nucleotidase in skeletal
muscle of animals has been reported to be 19 µmol/L for the
purified muscle enzyme,14 which is markedly
higher than the observed dialysate concentration of AMP at rest and
during exercise (from 0.05 to 3 µmol/L). Therefore, it is likely that
the formation of adenosine is regulated, at least in part, by
the availability of the substrate. The source of muscle
interstitial adenine nucleotides remains to be
elucidated, but nerve endings may be a likely
origin.15
Although adenosine has been proposed to be involved in the
regulation of many processes of importance in human skeletal muscle
during exercise, such as blood flow, sympathetic
activity,16 and insulin-mediated glucose
uptake,17 an increase in adenosine in
contracting human skeletal muscle tissue has never before been
demonstrated. The present study shows that adenosine is
present in the human muscle interstitium and that the concentration of
interstitial adenosine is associated with exercise
intensity, muscle blood flow, and vascular conductance. Furthermore,
the interstitial concentrations of the adenosine
precursors AMP, ADP, and ATP are increased in parallel with
adenosine, showing that the substrate for the ecto form of AMP
5'-nucleotidase is available to allow for an extracellular formation of
adenosine.
Received January 28, 1998;
revision received May 1, 1998;
accepted May 6, 1998.
2.
Dobson JG, Rubio R, Berne RM. Role of adenine
nucleotides, adenosine and inorganic phosphate in
the regulation of skeletal muscle blood flow. Circ Res. 1971;29:375–384.
3.
Drury AN, Szent-Györgyi A. The
physiological activity of adenine compounds with
special reference to their action upon the mammalian heart.
J Physiol. 1929;68:213–236.
4.
Schrader J, Berne RM, Rubio R. Uptake and
metabolism of adenosine by human erythrocyte
ghosts. Am J Physiol. 1972;223:159–166.
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Tullson P, Bangsbo J, Hellsten Y, Richter E. IMP
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B. Dynamic knee extension as a model for the study of an isolated
exercising muscle in man. J Appl Physiol. 1985;59:1647–1653.
8.
Scheller D, Kolb J. The internal reference technique
in microdialysis: a practical approach to monitoring dialysis
efficiency and to calculating tissue concentration from dialysate
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© 1998 American Heart Association, Inc.
Brief Rapid Communications
Adenosine Concentrations in the Interstitium of Resting and Contracting Human Skeletal Muscle
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Adenosine has
been proposed to be a locally produced regulator of blood flow in
skeletal muscle. However, the fundamental questions of to what extent
adenosine is formed in skeletal muscle tissue of humans,
whether it is present in the interstitium, and where it exerts its
vasodilatory effect remain unanswered.
Key Words: blood flow • exercise • adenosine • muscles • interstitium
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
In skeletal muscle,
the match between oxygen demand and blood flow is closely regulated,
with a linear relationship between work intensity and blood
flow.1 This precise regulation of blood flow has
been proposed to involve locally produced vasoactive metabolites, such
as adenosine.2 3 Traditionally, the
metabolism of compounds in human skeletal muscle has been
assessed by determinations of arteriovenous concentration differences
over the muscle and measurements made on muscle tissue samples.
However, largely because of a rapid uptake of adenosine by
several cell types, such as erythrocytes4 and
endothelial cells,5 measurements
of adenosine in blood have provided little information
regarding adenosine metabolism in human muscle.
Moreover, determinations of purine compounds in human muscle biopsies
have not demonstrated a significant elevation in adenosine
during exercise.6 The muscle interstitium is a
highly relevant compartment for indicating the concentrations of
adenosine in the muscle, because this is the site at which it
exerts several of its actions by binding to adenosine receptors
on the surface of vascular and skeletal muscle cells. In the
present study, the interstitial adenosine and
adenine nucleotide concentrations were examined in human
muscle with dialysis probes inserted into the vastus lateralis muscle.
The adenosine levels were compared with the magnitude of leg
blood flow at rest and during contraction.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Experimental Protocol
Seven healthy male subjects were informed of the experimental
procedures before giving their informed consent. After local
anesthesia, a 14-gauge cannula was inserted 2 to 3 cm into
the distal part of the musculus vastus lateralis in a direction
parallel to the muscle fiber orientation. The dialysis probes
(described below) were introduced into the muscle via the cannula.
After 1 hour of rest, the first dialysis perfusate samples were
collected, and then the subjects performed 5 bouts of dynamic knee
extensor contractions on a modified Krogh
ergometer.7 The exercise bouts consisted of five
15-minute work periods, separated by 15 minutes of rest, performed in
random order at work rates of 10, 20, 30, 40, and 50 W.
The dialysis probes consisted of a 4-cm-long semipermeable
dialysis membrane (cutoff, 5000 to 6000 Da; ID, 0.20 mm; OD,
0.22 mm) attached at both ends to hollow nylon tubes (ID,
0.50 mm; OD, 0.63 mm). The probes were perfused at a rate of
5 µL/min with a Ringer's acetate solution (pH 5.6) containing
0.5 mmol/L lactate and 3 mmol/L glucose. Dialysate (outflow)
was collected at rest and during the last 10 minutes of each work rate.
To determine the relative exchange of adenosine over the
dialysis membrane, [2-3H]adenosine
(<0.1 µCi/mL) was included in the perfusate. Scintillation
fluid was added to the samples, which were counted in a liquid
scintillation counter. The relative loss (recovery) of
adenosine
(RL=InDPM-OutDPM/InDPM)
at rest and at 10, 20, 30, 40, and 50 W was 60±8%, 65±5%, 64±5%,
61±4%, 60±4%, and 60±4%, respectively. The
interstitial adenosine concentrations (I) were
calculated on the basis of the perfusate (inflow) and dialysate
(outflow) concentrations, as well as recovery of each microdialysis
probe, according to the following equation:
I=(Out-In/RL)+In.8
Leg blood flow was determined by ultrasound
Doppler.9
Adenosine, AMP, ADP, and ATP in perfusate and
dialysate were quantitatively analyzed with reverse-phase
high-performance liquid
chromatography.10
Differences between means were determined with a 1-way
repeated-measures ANOVA. Significance was set at
P<0.05.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
The interstitial concentration of adenosine in
the muscle at rest was 220±100 nmol/L. During knee extensor exercise
at 10 W, the interstitial adenosine concentration
was higher (P<0.05), and it was further elevated with
increasing work rates (Figure
, panel a).
View larger version (13K):
[in a new window]
Figure 1. Concentration of (a) adenosine (n=7) in human
skeletal muscle interstitial fluid and (b) ATP ( 
, n=6),
ADP (
, n=5), and AMP (
, n=7) measured in dialysate. c, Femoral
arterial blood flow. Measurements were made at rest and
during graded dynamic knee extensor exercise. Data are mean±SEM.
*Adenosine, ATP, and blood flow; #ADP; and §AMP denote
significant difference (P<0.05) between successive work
rates.
, panel b). , panel c).
Vascular conductance was estimated on the basis of the measured leg
flow values and values for blood pressure obtained in a similar study
using the same exercise model.1 Estimated
conductance was 2.0, 22.2, 28.3, 35.3, 38.8, and 40.4 mm Hg
· min-1 · mL-1
at rest and during work rates of 10, 20, 30, 40, and 50 W,
respectively. The correlation coefficients for the
interstitial adenosine concentration and leg blood
flow or estimated vascular conductance were r=0.98
(P<0.001) and r=0.97 (P<0.01),
respectively.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The present study shows, for the first time,
interstitial concentrations of adenosine and its
adenine nucleotide precursors in resting and contracting
human skeletal muscle. The muscle interstitial
adenosine concentration was measured with a microdialysis
technique, and an average adenosine concentration of 220 nmol/L
was found at rest. This value is of the same magnitude as that
previously reported for interstitial canine cardiac muscle
adenosine concentrations (100 to 220 nmol/L), values estimated
from measurements of coronary arteriovenous adenosine
concentration differences and blood flow.5 
5-fold increase from rest
to a light work rate of 10 W. When exercise was performed at 20, 30,
40, or 50 W, the concentration was moderately greater for each
increment. The pattern was similar to the response in blood flow as
well as estimated vascular conductance. These findings provide support
for the proposition that adenosine is of importance in muscle
vasodilation. The nonlinear increase in the interstitial
adenosine concentration could be explained by a multicomponent
regulation of muscle blood flow, in which adenosine may act in
synchrony with other vasoactive substances.
Acknowledgments
This study was supported by the Danish Natural Research
Foundation (Jnr 504-14).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Andersen P, Saltin B. Maximal perfusion of
skeletal muscle in man. J Physiol (Lond). 1985;366:233–249.
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R. J. Fox and M. D. Frame Regulation of flow and wall shear stress in arteriolar networks of the hamster cheek pouch J Appl Physiol, May 1, 2002; 92(5): 2080 - 2088. [Abstract] [Full Text] [PDF]
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