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Copenhagen Muscle Research Center, Departments of 1 Anesthesia and 2 Hepatology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We evaluated whether the increase in blood lactate with intense exercise is influenced by a low hepatosplanchnic blood flow as assessed by indocyanine green dye elimination and blood sampling from an artery and the hepatic vein in eight men. The hepatosplanchnic blood flow decreased from a resting value of 1.6 ± 0.1 to 0.7 ± 0.1 (SE) l/min during exercise. Yet the hepatosplanchnic O2 uptake increased from 67 ± 3 to 93 ± 13 ml/min, and the output of glucose increased from 1.1 ± 0.1 to 2.1 ± 0.3 mmol/min (P < 0.05). Even at the lowest hepatosplanchnic venous hemoglobin O2 saturation during exercise of 6%, the average concentration of glucose in arterial blood was maintained close to the resting level (5.2 ± 0.2 vs. 5.5 ± 0.2 mmol/l), whereas the difference between arterial and hepatic venous blood glucose increased to a maximum of 22 mmol/l. In arterial blood, the concentration of lactate increased from 1.1 ± 0.2 to 6.0 ± 1.0 mmol/l, and the hepatosplanchnic uptake of lactate was elevated from 0.4 ± 0.06 to 1.0 ± 0.05 mmol/min during exercise (P < 0.05). However, when the hepatosplanchnic venous hemoglobin O2 saturation became low, the arterial and hepatosplanchnic venous blood lactate difference approached zero. Even with a marked reduction in its blood flow, exercise did not challenge the ability of the liver to maintain blood glucose homeostasis. However, it appeared that the contribution of the Cori cycle decreased, and the accumulation of lactate in blood became influenced by the reduced hepatosplanchnic blood flow.
anaerobic threshold; Cori cycle; glucose; hepatic blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PROGRESSIVE INCREASE IN blood lactate with exercise intensity is sometimes considered to be a reflection of anaerobic metabolism. However, muscle, even when working at a high intensity, may take up lactate (43). The blood lactate level is also influenced by the metabolism in other organs, including "resting" skeletal muscle (23), the heart (10), the brain (25), the kidneys (29), and notably the liver (42).
In response to low-intensity exercise, the hepatic extraction of lactate increases (2), despite a reduced blood flow (4, 41, 42). Yet a marked reduction in the hepatosplanchnic blood flow challenges the metabolic function of the liver (38). We hypothesized that the marked increase in blood lactate with intense exercise is influenced by a reduced uptake by the liver, even to an extent that it may affect gluconeogenesis. After an overnight fast, approximately one-third of the glucose production is by hepatic gluconeogenesis (24). On the other hand, the influence of exercise is controversial in humans, as hepatic gluconeogenesis has been reported both to increase (8) and to decrease (12). Friedlander et al. (14) suggested that the plasma clearance of lactate for the purpose of hepatic gluconeogenesis is reduced after training, indicating that a limited blood flow to liver affects its uptake of lactate. In the dog, the liver demonstrates a net release of lactate in response to exercise (15, 48). It is not known whether hepatic uptake of lactate is attenuated during intense exercise in humans or whether the liver releases lactate.
In healthy humans, we evaluated the concentration difference for
lactate between arterial and hepatic venous blood and estimated the
hepatosplanchnic blood flow and O2 uptake
(
O2) during exercise. We aimed for a
work intensity that the subjects could maintain for ~30 min. Such a
work rate was considered to elicit a significant accumulation of
lactate in arterial blood and at the same time allow for an acceptable
approximation to steady-state elimination of indocyanine green (ICG).
To exclude an influence of exercise-induced arterial hypoxemia
(13, 32) on hepatic metabolism, the evaluation was carried
out with an inspired O2 fraction of both 0.21 and 0.30.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Eight male subjects (Table 1)
participated in the study after giving informed consent as approved by
the Ethics Committee of Copenhagen (KF 01-276/97). None of the
subjects had any diseases or injury 3 wk before the experiment, nor
were they taking any medication. All subjects were studied in the
resting state 10-12 h after an overnight fast. The subjects
abstained from physical training, alcohol, and tobacco smoking on the
day before the experiments, which began at 8:00 AM.
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A catheter (1.0 mm ID; 20 gauge) was inserted in the brachial artery of
the nondominant arm. A liver venous catheter (Cournand, 7 Fr) was
introduced via the right median cubital vein and was guided by with the
subject supine. The position of the catheter was confirmed with
fluoroscopy in the body position used during cycling. To ensure that
ventilation (E) did not displace the catheter,
the position was also confirmed after maximal voluntary E. The catheters were kept patent by continuous
infusion of isotonic saline (3 ml/h) and were connected to a pressure
monitoring kit (Baxter Healthcare, Maurepas, France) positioned at the
level of the heart.
Maximal pulmonary O2
(O2 max) was determined several days
before the experiment. An incremental protocol using a modified Krogh
cycling ergometer with the upper body in a 45° position
(16) was used. On the day of the experiment, the same type
of semisupine exercise was used. Pedaling was maintained at a rate of
60 rpm throughout the 30 min of exercise while aiming at a
O2 corresponding to ~75% of
O2 max (Table 1). The subjects were
randomized to an inspired O2 fraction of 0.21 or 0.30 in a
double-blind fashion by using a crossover study design with 1 h of
recovery between trials. After each exercise session, perceived
exertion was expressed according to a visual Borg scale (9).
For description of hepatic blood flow, O2 uptake, and blood
variables obtained from the hepatic vein, we used the term
"hepatosplanchnic" to indicate that blood from the hepatic vein
also represents portal blood, whereas ICG is eliminated exclusively by
the liver. For the assessment of hepatosplanchnic blood flow, a
constant infusion of ICG (0.18 ± 0.02 µmol/l; Cardio-Green;
Becton Dickinson, Cockeysville, MD) was administered into an arm vein
by a peristaltic roller pump (type 104; Ole Dich, Hvidovre, Denmark). A
45-min priming infusion secured a steady-state plasma concentration of
ICG. Arterial and hepatic venous blood were collected simultaneously
five times with a 3-min interval between samples. This procedure was
performed in the last 15 min of the resting period and again in the
last 15 min of exercise. Immediately on completion of the study, the samples were centrifuged, and plasma was frozen at 
20°C. The ICG
dye concentration was determined by high-performance liquid chromatography with a detection limit of 0.01 µmol/l
(34).
The estimated mean hepatosplanchnic blood flow at rest and during
exercise was calculated as [IR (VdICG · dCa/dt)]/{(Ca Cv) · [1/(1 Hct)]}, where IR is the infusion rate
of ICG; Ca and Cv are the concentrations of ICG in the brachial artery and in the hepatic vein, respectively; dCa/dt is the Ca
accumulation rate; VdICG is the volume of distribution
of ICG; dCa/dt × VdICG represents a
correction for minor deviations from steady-state conditions
(33); and Hct is the hematocrit.
VdICG was estimated as 0.05 × body weight (kg),
and dCa/dt was expressed as the linear regression for the
five samples (44). This correction factor was not used
when blood flow was calculated at each time point. In this case, the
hepatosplanchnic O2 was calculated by
using the Fick principle based on the O2 content. In the
subject with the lowest hemoglobin O2 saturation obtained
in the hepatic vein during cycling, determination of ICG failed. In two
subjects, the hepatosplanchnic blood flow at rest was ~3 l/min as
found after a meal (36), and blood flows from these two
subjects were excluded from the overall presentation because of
suspicion of protocol violation. However, in both cases, the flow
became reduced by 50% during exercise associated with an increase in
the hepatosplanchnic O2, i.e., these
subjects showed the same pattern as found for the others.
The subjects breathed through a two-way low-resistance T valve (model
2700; Hans Rudolph, Kansas City, MO) with humidified air delivered from
a Douglas bag. The determinations of the flow rate and gas analysis
were made continuously by using a cardiopulmonary exercise test system
(2001; Medical Graphics, St. Paul, MN). Measurements were made on-line
with electrochemical O2 and CO2 infrared
analyzers. After 5 min of rest to stabilize E, the
subject breathed ambient air and thereafter air with an inspired
O2 fraction of either 0.21 or 0.30 for 5 min while being
monitored in the exercise position. Measurements of
O2, E, the
respiratory rate, expired CO2, respiratory exchange ratio,
and end-tidal partial pressures for O2 and CO2
were averaged for every 30 s.
Cardiac output was estimated by an impedance cardiograph (CDM 3000 Hemodynamics Monitor, Cardiodynamics International, San Diego, CA). Two disposable electrodes (Blue Sensor VL-00-S, Medicotest, Ølstykke, Denmark) were placed over the sternocleidomastoid muscle on each side. Also in the midaxillary line, a pair of electrodes was placed at the level of the umbilicus on both sides of the body. Cardiac output was calculated from pulsatile changes in thoracic electrical impedance (36, 47). Heart rate and mean arterial pressure were assessed invasively (Baxter), and results are expressed as the average, both at rest and during exercise.
Paired samples of arterial and hepatosplanchnic venous blood were obtained at rest and after 18, 24, and 30 min of exercise by using heparinized syinges (QS50; Radiometer, Copenhagen, Denmark). Blood samples were kept on ice until analysis for blood-gas variables, acid-base status, and the glucose concentration by using an ABL apparatus (model 615; Radiometer). The concentration of lactate in plasma was determined by a YSI (model 2300; Yellow Springs Instruments). The blood O2 content was calculated as the sum of bound and dissolved O2.
Blood samples for assessment of plasma catecholamines were obtained at
rest and during the last minute of exercise. Plasma was separated
immediately and frozen. The catecholamine concentrations were
determined by a single-isotope radioenzymatic method (6) by using high-performance liquid chromatography (Waters Chromatography Division, Millford, MA) with an average variability of 1%
(31). The intrinsic hepatic clearance of a substance was
[hepatosplanchnic blood flow · (1 Hct) · ln(Cv/Ca)], which is equivalent to the permability-surface product and reflects the ability of the liver to
extract a substance from plasma (27, 33). If the
permeability of the membrane of the liver cell remains unchanged, the
intrinsic clearance is a measure of the sinusoidal surface area
(27, 33).
Data are expressed as means with standard error of the mean. Comparisons among multiple samples were evaluated by the Friedman analysis of variance (SYSTAT). Significant effects were further evaluated by a Wilcoxon test by rank for locating significant paired differences. A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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E and circulation.
Cycling resulted in elevated E associated with
increased expired CO2 and O2
(Fig. 1) and changes in the end-tidal
variables (Table 2). Thus the respiratory exchange ratio
increased during exercise to establish a plateau (Fig. 1). Cardiac
output, heart rate, and mean arterial pressure also increased (Table
2).
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O2 was elevated from 67 ± 3 ml/min
at rest to 93 ± 13 ml/min during exercise (P < 0.05). When determined for each time point, it appeared that the
hepatosplanchnic blood flow was lowest at the end of the exercise trial
(Fig. 2).
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Blood-gas variables. The arterial CO2 pressure increased, and the hepatic venous CO2 partial pressure was even higher than in arterial blood (Table 2). The arterial O2 partial pressure did not change from the resting level. Also, the arterial hemoglobin O2 saturation was not affected by exercise, whereas hematocrit and, therefore, the arterial O2 content increased. During cycling, the hemoglobin O2 saturation in hepatic venous blood decreased and reached a lowest level of 6% in one subject. Furthermore, pH values of arterial and hepatic venous blood were reduced. The average O2 concentration difference between arterial and hepatic venous blood increased from 40 ± 3 ml/l at rest to 142 ± 13 ml/l during exercise.
Substrates.
The glucose level obtained in the hepatic vein increased markedly
during exercise, with no significant change in the average glucose
concentration in arterial blood (Table 2). Yet after 24 min of
exercise, the glucose level in arterial blood became lower than at rest
(Fig. 3). The hepatic venous and the
arterial blood glucose concentration difference increased during
exercise and reached a maximum of 22 mmol/l when the hemoglobin
O2 saturation in the hepatic vein became low (Fig.
4). The hepatosplanchnic glucose release
increased from a resting level of 1.1 ± 0.05 to 2.1 ± 0.26 mmol/min (P < 0.05).
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Intrinsic clearance. The hepatic intrinsic clearance of catecholamines was not significantly affected by exercise. The intrinsic clearance of ICG declined from 2,592 ± 175 to 774 ± 33 ml/min and that of lactate was reduced from 27.4 ± 4.1 to 10.2 ± 3.5 l/min (P < 0.05).
Inspired O2 fraction of 0.30. Perceived exertion decreased from 18 (15-19) in normoxia to 16 (13-17) (median and range) during exercise in hyperoxia (P < 0.05). Respiratory variables were not affected by an increased inspired O2 fraction, whereas the arterial O2 pressure was higher than during control exercise (Table 2). The acid-base status, the concentrations of hemoglobin and the plasma catecholamines, and the concentration of glucose were not affected by hyperoxia. Although the concentration of lactate tended to be lower, it did not reach statistical significance. Both arterial and hepatic venous O2 saturations were higher than during control exercise. The O2 contents in arterial and hepatic venous blood were elevated, but O2 content difference between arterial and hepatic venous blood was not influenced by hyperoxia.
The hepatosplanchnic blood flow was not different from that obtained during exercise with an inspired O2 fraction of 0.21. Furthermore, the hepatosplanchnicO2
(Table 2) and the hepatosplanchnic release of glucose (2.2 ± 0.3 mmol/min) and uptake of lactate (1.1 ± 0.14 mmol/min) reached
similar values as those established during exercise in normoxia. In
addition, hyperoxia did not change hepatic intrinsic clearance of
lactate or that of catecholamines.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that, despite a marked reduction in the hepatosplanchnic blood flow during exercise in humans, the liver maintained its metabolic functions, as indicated by an increased hepatosplanchnic venous-arterial glucose difference and an almost constant level of glucose in arterial blood. However, when the hepatosplanchnic blood flow reached a minimum and was associated with a reduction in hepatic venous O2 saturation to 6%, the contribution of the Cori cycle to glucose production appeared to collapse. Thus an exercise intensity associated with a reduction in the hepatosplanchnic uptake of lactate would contribute to the accumulation of lactate in arterial blood.
A reduced uptake of lactate challenges the assumption that the increased blood lactate level during exercise reflects anaerobic metabolism in working skeletal muscle. With a moderate reduction of hepatosplanchnic blood flow, the concentration difference between arterial and hepatosplanchnic venous lactate increased to ~1.5 mmol/l and was associated with an arterial concentration close to the 4 mmol/l, i.e., identical to the definition of the so-called "anaerobic threshold" (5). When this level is surpassed, the concentration difference between arterial and hepatosplanchnic venous lactate was close to zero. Thus intense exercise approaches the physiology described during hemorrhage (38), for which a marked blood loss is associated with enhanced lactate production, both by the liver and the kidneys (38).
Hepatosplanchnic blood flow and O2
during exercise.
We observed a >50% reduction in hepatosplanchnic blood flow
concomitant with an increase in hepatosplanchnic
O2 by 36%. Others have documented this
magnitude of exercise-induced reduction in hepatosplanchnic blood flow,
although indirect techniques were used (40). With a bolus
injection of ICG and measurements of the systemic ICG concentrations,
Rowell et al. (41) and Clausen and Trap-Jensen
(11) reported that exercise reduces the fractional clearances of ICG to between 19 and 93% of the resting value, even in
nonfasting subjects. With a similar technique to calculate hepatosplanchnic blood flow, Kjaer et al. (28) report a
reduction from 0.8 to 0.4 l/min during exercise in fasting subjects.
Although the relative changes correspond to the present results, the
absolute values seem to be underestimated. The bolus technique is based on the assumption that the hepatic extraction of ICG is 1.00 (33), but the hepatic extraction could be as low as
60-70% (20, 27). Thus with the use of constant
infusion of ICG and blood sampling from the artery and the hepatic
vein, the resting hepatosplanchnic blood flow has been estimated to be
1.1-1.7 l/min (2-4, 7, 11, 36, 39). By using
this technique during exercise, the reduction of hepatosplanchnic blood
flow is up to 50% (3, 4, 7, 11), even after a meal
(36).
O2 during exercise. It was demonstrated
that the hepatosplanchnic O2 increased from 74 ml/min at the initial stage of moderate exercise to 93 ml/min
at the end of exercise (1 h, ~60%
O2 max), but baseline values were not
presented. With a more prolonged exercise protocol, the
hepatosplanchnic O2 increased to 120%
of the resting level, whereas the hepatosplanchnic blood flow remained
constant (2). These results appear to be in agreement with
the present data, supporting the observation that the liver is able to
enhance its O2, despite a reduction in
blood flow.
An increase in hepatosplanchnic O2 is
suggested to arise from the glycogenolytic and gluconeogenic activities
of the liver. With the use of stable isotopes during a fast,
30-66% of the hepatic glucose production is related to
gluconeogenesis (24). The twofold increase in total
production of glucose (7) is also related to enhanced
gluconeogenesis during exercise (8). This was achieved at
an exercise intensity associated with a concentration of lactate in
arterial blood of ~4 mmol/l (8). At that level, the
present data correspond to those of Bergman et al. (8) as
the liver increases its uptake of lactate, presumably as part of the
Cori cycle. However, with a further reduction in the hepatosplanchnic blood flow, the Cori cycle appears to be attenuated, supporting findings by Coggan et al. (12).
The present observations are based on the concentration difference for
lactate between arterial and hepatic venous blood, and we do not have
any further evidence for gluconeogenesis in the liver. One
consideration is that a low blood flow to splanchnic organs reduces pH
in the tissue, probably because of enhanced anaerobic metabolism
(26). Another consideration is that enhanced glycogenolysis may lead to formation of lactate. However, as in the
present study, Bergeron et al. (7) found that the level of
glucose remained stable almost throughout the experiment. However, after 24 min of exercise, arterial blood glucose was reduced to 4.8 mmol/l, indicating that the metabolic function of the liver can be
challenged by strenuous exercise.
Whether sympathetic nervous activity is of importance for attenuation
of hepatic gluconeogenesis and an upregulation of glycogenolysis is not
known. The hepatic artery is provided with both 
- (22) and 
-receptors (21). With a high concentration of
epinephrine, the hepatic production of glucose increases, partly
because of an increased supply of gluconeogenic substrates (alanine)
and partly related to a direct action on the liver cells
(45). On the other hand, exercise with -receptor
blockade results in diminished hepatic uptake of gluconeogenic
precursors, decreased lactate uptake, and increased glucose output
(3). Gleeson (17) suggested that interleukins
released from the working muscles during exercise are important for
glucose production in the liver.
Hepatic sinusoidal collapse. With a reduction in hepatosplanchnic blood flow, the available number of hepatic sinusoids may decrease. In the cat, "derecruitment" of the hepatic sinusoids takes place when the hepatic blood flow is reduced to a similar extent as during exercise (19). In fact, norepinephrine reduces the blood volume of the liver (40), and also the plasma volume in the hepatic sinusoids may be affected (20). With a 30 and 40% blood loss during hemorrhage in the pig, hepatic norepinephrine uptake decreases, suggestive of a partial sinusoidal collapse (38). A reduced intrinsic hepatic clearance of ICG found during exercise in the present study suggests that the active sinusoidal area is reduced in response to exercise in humans.
Hyperoxia.
During submaximal exercise, hyperoxia does not affect
O2 (1, 37, 46), but a
lowered concentration of lactate in arterial blood appears to be a
consistent finding (18, 30, 46). The enhanced exercise
performance with hyperoxia (35, 37, 46) is related to a
higher oxidation rate for pyruvate, limiting the accumulation of
lactate (30). From the present data, a reduced level of
lactate in blood during exercise with hyperoxia is not related to an
enhanced hepatic uptake of lactate.
O2,
although blood supply was reduced by >50% during exercise. The
hepatosplanchnic exchange of lactate, glucose, and catecholamines did
not become flow dependent, even in the face of a reduction of the
sinusoidal surface area. Despite the reduction in hepatosplanchnic
blood flow during exercise, the liver is able to upregulate its
metabolic function, yet the Cori cycle appears to decrease its
importance for blood glucose homeostasis.
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ACKNOWLEDGEMENTS |
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Dr. Mario Perko is thanked for the loan of the impedance cardiograph.
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FOOTNOTES |
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H. B. Nielsen was funded by the Copenhagen Muscle Research Center. This study was supported by The Danish National Research Foundation (Grant #504-14).
Address for reprint requests and other correspondence: H. B. Nielsen, Dept. of Anesthesia 2041, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark (E-mail: h.bay{at}dadlnet.dk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.00028.2001
Received 10 January 2001; accepted in final form 11 November 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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