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1 Department of Medicine, 2 Department of Infectious Diseases, 3 The Copenhagen Muscle Research Center Rigshospitalet, and 4 National University Hospital and Department of Clinical Physiology, Bispebjerg Hospital, University of Copenhagen, 2100 Copenhagen, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We assessed the hypothesis that the epinephrine surge present during sepsis accelerates aerobic glycolysis and lactate production by increasing activity of skeletal muscle Na+-K+-ATPase. Healthy volunteers received an intravenous bolus of endotoxin or placebo in a randomized order on two different days. Endotoxemia induced a response resembling sepsis. Endotoxemia increased plasma epinephrine to a maximum at t = 2 h of 0.7 ± 0.1 vs. 0.3 ± 0.1 nmol/l (P < 0.05, n = 6-7). Endotoxemia reduced plasma K+ reaching a nadir at t = 5 h of 3.3 ± 0.1 vs. 3.8 ± 0.1 mmol/l (P < 0.01, n = 6-7), followed by an increase to placebo level at t = 7-8 h. During the declining plasma K+, a relative accumulation of K+ was seen reaching a maximum at t = 6 h of 8.7 ± 3.8 mmol/leg (P < 0.05). Plasma lactate increased to a maximum at t = 1 h of 2.5 ± 0.5 vs. 0.9 ± 0.1 mmol/l (P < 0.05, n = 8) in association with increased release of lactate from the legs. These changes were not associated with hypoperfusion or hypoxia. During the first 24 h after endotoxin infusion, renal K+ excretion was 27 ± 7 mmol, i.e., 58% higher than after placebo. Combination of the well-known stimulatory effect of catecholamines on skeletal muscle Na+-K+-ATPase activity, with the present confirmation of an expected Na+-K+- ATPase-induced decline in plasma K+, suggests that the increased lactate release was due to increased Na+-K+-ATPase activity, supporting our hypothesis. Thus increased lactate levels in acutely and severely ill patients should not be managed only from the point of view that it reflects hypoxia.
K+ homeostasis; sepsis; glycolysis
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PATIENTS WITH TRAUMA or sepsis hyperlactacidemia are
usually managed from the point of view that it reflects anaerobic
glycolysis caused by tissue hypoxia. However, it has been suggested
that increased activity of skeletal muscle
Na+-K+-ATPase caused by the epinephrine surge
present in such patients causes aerobic glycolysis and lactate
production (12, 13), i.e., the production of 2 mol ATP by
glycolysis compared with 38 mol by complete oxidation of 1 mol of
glucose may not be a consequence of anaerobic conditions, but an effect
linked to the Na+-K+-ATPase activity. This
hypothesis is favored by several observations. First, a 46% increase
in Na+-K+-ATPase activity has been observed in
extensor digitorum longus muscles from septic rats (22).
Second, in well-oxygenated skeletal muscles, increased
Na+-K+-ATPase activity induced by monensin
(12), epinephrine, amylin (14), or insulin
(21) leads to increased lactate production, and, on the
other hand, inhibition of the Na+-K+-ATPase by
ouabain or reduced extracellular K+ concentration reduces
lactate production (14). Third, increased skeletal muscle
Na+-K+-ATPase activity is induced by increased
catecholamine levels that are present in trauma and sepsis. Fourth, a
positive correlation between plasma lactate and plasma catecholamine
concentrations has been observed and a reduction or blockage of
hyperlactacidemia can be achieved by adrenergic blockage (for a review,
see Ref. 13). If an increased catecholamine level is
responsible for a part of the increase in blood lactate level in
traumatized or septic patients, this has to be taken into account
because it may be present in patients after compromised perfusion and
tissue oxygen delivery have been normalized. It is well known that the catecholamine stimulation of the skeletal muscle
Na+-K+-ATPase is achieved via
2-adrenoceptors (2), and that increased activity of the Na+-K+-ATPase, caused by
pumping Na+ out and K+ into the cell in a 3:2
relationship, leads to increased cellular K+ uptake
(2). This may lead to hypokalemia, which is actually a
frequent finding at admission of severely ill patients (5, 19). Furthermore, a catecholamine-induced increase in
Na+-K+-ATPase activity may not only
induce skeletal muscle K+ uptake, but catecholamines may
also via 
- and -adrenoceptors alter renal tubular
Na+-K+-ATPase activity (11) and
thus affect renal K+ excretion.
Several observations favoring the hypothesis that catecholamine stimulation of Na+-K+-ATPase secondary leads to lactate production, comes from studies of isolated cells and animal models, whereas studies in humans have not been reported. Therefore, in the present study, we assessed the effect in humans of endotoxin on the K+ homeostasis and lactate concentration changes to evaluate the hypothesis that the endotoxin-induced increase in epinephrine level leads to increased blood lactate level and hypokalemia under aerobic conditions.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Volunteers
Eight healthy young volunteers (21-25 yr, 77 ± 3 kg body wt) were studied. None of the subjects had a history of medical problems, and physical examination revealed no abnormalities. Blood analyses showed normal hemoglobin, white blood cell count (WBC), WBC differential count, C-reactive protein (CRP), and blood glucose as well as normal kidney function (urea and creatinine), normal liver function (alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase), normal coagulation system [activated partial thromboblastin time, antithrombin III, prothrombin time, and international normalized ratio (INR)], and normal thyroid-stimulating hormone. All had a normal ECG. The volunteers did not use any medication, and they did not have any febrile illness in the 2 wk preceding the study.Study Design
The presently used study design has previously been described in detail (18). In brief, the study was performed in an intensive care unit setting under the continuous supervision of an anesthesiologist, with emergency and resuscitation equipment immediately available. The volunteers were studied after endotoxin infusion and at least 14 days apart after placebo infusion. The sequence endotoxin/placebo was randomly chosen. Because of the obvious symptomatic (temperature and blood pressure) changes after infusion of endotoxin, neither the volunteers nor the staff was blinded to the study protocol.The volunteers fasted overnight before endotoxin or placebo
administration. Rectal temperature was recorded continuously. Furthermore, the subjects were monitored with respect to blood pressure
(by a radial artery catheter) and heart rate. A femoral vein was
catheterized for blood sampling. Isotonic saline solution was infused.
From 8 AM until 8 PM, isotonic glucose (50 mg · kg
1 · h1)
was continuously infused. Subjects were given an intravenous bolus of
endotoxin from Escherichia coli (lot EC-6, United States Pharmacopia Convention; Rockville, MD) of 2 ng/kg body wt at
t = 0, where t is time. The study was
approved by the regional scientific ethical committee (no. 01-144/98)
and written informed consent was obtained from each volunteer.
Blood and Urine Sampling
Blood was drawn at t = 0 and at 2, 4, 8, 10, 24, and 32 h after injection for differential WBC counts, CRP, hemoglobin, and plasma electrolytes. Blood was taken for chemical analyses of liver and kidney function at the same time points, except at t = 2 h. Blood for measurements of cortisol, adrenocorticotropin (ACTH), insulin, orosomucoid, and fibrinogen was drawn at t = 0, 4, and 32 h and at t = 8, 10, and 24 h for orosomucoid and fibrinogen only. Blood for isolation of serum and plasma was drawn at t = 0, 2, 4, 8, 24, and 32 h. Blood samples were obtained simultaneously from the femoral vein and the radial artery at t = 0, 1, 2, 3, 4, 5, 6, 7, 8, and 10 h for measurements of plasma K+, Na+, lactate, pH, PO2, PCO2, glucose, as well as blood hemoglobin and oxygen saturation. These parameters were measured with the use of a blood gas analyzer (model ABL605, Radiometer), except for plasma lactate, which was automatically analyzed enzymatically with lactate dehydrogenase (Cobas Fara, Roche; Basel, Switzerland). The volunteers were encouraged to empty the bladder just before endotoxin was injected, and urine was collected for the period t = 0-24 h.Analyses
Catecholamines.
Blood samples for measurements of epinephrine and norepinephrine were
drawn into ice-cold glass tubes containing EGTA glutathione. Plasma was
stored at 
80°C until analyzed by high-performance liquid
chromatography (Hewlett-Packard; Waldbronn, Germany) with electrochemical detection as previously described (10).
Tumor necrosis factor-.
Blood samples were drawn into ice-cold tubes containing EDTA and
trasylol and then spun immediately at 2,200 g for 15 min at
4°C. Plasma was stored at 80°C until analyzed. Tumor necrosis factor- (TNF-) was determined with the use of an ELISA kit
(detection limit 0.5 pg/ml, R&D Systems; Minneapolis, MN). According to
the manufacturer, the TNF- ELISA kits are insensitive to the
addition of recombinant forms of the soluble receptor, and the
measurements therefore correspond to both soluble and receptor-bound
cytokine. All cytokine determinations were run as duplicates, and mean
values were calculated.
Clinical chemistry tests. Standard laboratory procedures were employed. Urine and plasma K+ were measured with a potentiometer (model 917, Hitachi). Only plasma K+ measurements obtained from the Hitachi 917 at t = 24 and 32 h are given in RESULTS.
Leg blood flow. The femoral arterial leg blood flow (LBF) was measured at t = 0, and each hour until t = 8 h with the ultrasound Doppler technique, as previously validated (25). An ultrasound Doppler (model CFM 800; Vingmed Sound; Horton, Norway) equipped with an annular phased-array transducer probe 11.5-mm diameter (Vingmed Sound) operating at an imaging frequency of 7.5 MHz and the variable Doppler frequencies of 4.0-6.0 MHz (high-pulsed repetition frequency mode 4-36 kHz was used) (25).
Calculations and Statistics
K+ uptake in one leg was calculated as the arteriovenous plasma K+ difference multiplied by leg plasma flow [LBF × (1 hematocrit)]. Lactate release from one
leg was calculated as the venoarterial plasma lactate difference
multiplied by LBF. Accumulated K+ uptake was calculated as
the sum of K+ uptake each hour during the period of
interest. Difference in accumulated K+ uptake between the
two groups was calculated as the accumulated K+ uptake
after placebo subtracted from the accumulated K+ uptake
after endotoxin.
Statistical significance between measurements obtained at two or more
different time points after placebo and after endotoxin (paired design)
was ascertained by two-way repeated-measures ANOVA with SigmaStat for
Windows version 2.03 (SPSS). The two factors were treatment (placebo
vs. endotoxin) and time. After a statistically significant treatment
effect (or treatment times time interaction) was detected, a
multiple-comparison procedure (Tukey's test) was used to localize
significant differences at each time point. Measurements that were not
normally distributed were log transformed before statistical
assessment. Parameters measured only at baseline and once after
endotoxin infusion were compared with the use of Student's t-test for paired observations. Linear regression analysis
was performed using the method of the least squares. The squared
correlation coefficient (r2) and the coefficient
of inclination () are given. Results are given as means ± SE
or confidence interval as indicated. P values <0.05 were
considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Infusion of endotoxin significantly increased body temperature to
a maximum at t = 4 h of 39.1 ± 0.2 vs.
36.9 ± 0.2°C after placebo (P < 0.01, n = 8). This was followed by a gradual decline to
37.7 ± 0.1°C at t = 9 h. During the rise
in body temperature, the patients were shivering. At t = 5 h a maximum decline in mean arterial blood pressure from
95 ± 2 to 73 ± 2 mmHg (P < 0.01, n = 8) and at t = 4 h an increase
in heart rate from 65 ± 4 to a maximum of 97 ± 5 beats/min
(P < 0.01, n = 8) were observed. These
hemodynamic changes were associated with a maximum increase in LBF at
t = 0 from 450 ± 57 in the endotoxin group and
405 ± 38 ml/min (P > 0.6, n = 7)
in the placebo group to 731 ± 79 versus 533 ± 77 ml/min at
t = 5 h (P < 0.05, n = 7), respectively. The increased LBF level was
maintained after endotoxin infusion for the next 3 h. Laboratory
measurements on blood samples showed that maximum increases after
endotoxin versus placebo were the following: TNF- [964 vs. 3 pg/ml
(geometric mean) at t = 2 h] (Fig.
1), CRP (481 ± 62 vs. <48 mg/l at
t = 24 h, P < 0.01), orosomucoid (22 ± 2 vs. 16 ± 1 g/l at t = 32 h,
P < 0.01), fibrinogen (8.0 ± 0.4 vs. 6.3 ± 0.5 µmol/l at t = 32 h, P < 0.05), leucocyte count (13.0 ± 0.8 vs. 6.3 ± 0.4 109/l at t = 8 h, P < 0.01), and neutrophil count (12.1 ± 0.7 vs. 3.9 ± 0.4 109/l at t = 8 h, P < 0.01), plasma ACTH (79 ± 28 vs. 6 ± 1 pmol/l at
t = 4 h, P < 0.05), and plasma
cortisol (710 ± 101 vs. 295 ± 66 nmol/l at
t = 4 h, P < 0.01). The maximum
reductions were the following: lymphocyte count (0.5 ± 0.2 vs.
1.6 ± 0.1 109/l at t = 4 h,
P < 0.01) and monocyte count (0.05 ± 0.01 vs.
0.5 ± 0.1 109/l at t = 2 h,
P < 0.01). A significantly higher skeletal muscle glucose uptake was observed after endotoxin infusion compared with
placebo (data not shown). No significant changes were observed in
parameters analyzed for kidney and liver function, hemoglobin, plasma
Na+, plasma myoglobin, or plasma insulin between the two
groups. Taken together, the changes in temperature and in hemodynamic, immunologic, and hormonal parameters observed in response to infusion of endotoxin all resemble the acute response observed in patients with
severe infections caused by bacteria that produces endotoxin.
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Catecholamines
Infusion of endotoxin significantly increased the plasma epinephrine concentration to a maximum at t = 2 h of 0.7 ± 0.1 versus 0.3 ± 0.1 nmol/l (P < 0.05, n = 6-7) (Fig. 2) whereas only a tendency to an increase was seen in the plasma norepinephrine level (data not shown).
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Plasma K+
Infusion of endotoxin significantly reduced femoral venous plasma K+, reaching a nadir at t = 5 h of 3.3 ± 0.1 compared with 3.8 ± 0.1 mmol/l after placebo infusion (P < 0.01, n = 6-7) (Fig. 3A). After the nadir was reached, venous plasma K+ increased to the level measured after placebo infusion after another 2-3 h. Similar changes were seen in arterial plasma K+. At t = 8 h the initial plasma K+ level was reached and plasma K+ remained stable for the next 24 h in both groups. At t = 24 and 32 h, venous plasma K+ values after endotoxin and placebo were 3.8 ± 0.1 vs. 3.9 ± 0.1 mmol/l (P = 0.8, n = 8) and 3.7 ± 0.1 vs. 3.7 ± 0.1 mmol/l (P < 0.6, n = 8), respectively.
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K+ Exchange Across Leg
After placebo, venous plasma K+ was slightly higher than arterial plasma K+, which reflects a small K+ loss from the resting leg (Fig. 3, A and B). Until t = 5 h, the arteriovenous plasma K+ difference was numerically higher after placebo compared with endotoxin, reaching a maximum at t = 4 h of0.2 ± 0.1 versus 0.0 ± 0.1 mmol/l
(P < 0.05, n = 8) (Fig.
3B). In combination with the increased LBF this indicates
that until t = 5-6 h there was a reduced loss of
K+ from the leg after endotoxin infusion. On the basis of
arteriovenous plasma K+ differences and LBF measurements
obtained each hour after endotoxin and placebo infusions, the
accumulated transport of K+ to or from the leg could be
calculated (Fig. 4). After placebo infusion, the accumulated K+ exchange across the leg showed
a constant loss of K+ from the leg (linear regression
analysis; = 1.75 ± 0.13 mmol K/h,
r2 = 0.95, P < 0.01).
However, after endotoxin infusion, the loss of K+ from the
leg was reduced within the first hours. Thus the difference in
accumulated K+ (accumulated K+ after endotoxin
placebo) showed a gradual increase reaching a maximum after 6 h of
8.7 ± 3.8 mmol per leg (P < 0.05) (Fig. 4).
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Renal K+ Excretion
Urine volumes for the first 24 h after infusions were similar after endotoxin infusion (2,869 ± 253) and placebo infusion (2,788 ± 252 ml) (P > 0.7, n = 8). After endotoxin infusion urine K+ concentration was 27 ± 3 compared with 18 ± 2 mmol/l after placebo infusion, i.e., an increase of 50% (P < 0.05, n = 8). Thus during the first 24 h after endotoxin infusion, the total renal K+ excretion was 27 ± 7 mmol, i.e., 58% (P < 0.01) higher compared with placebo.Plasma Lactate and Oxygen Saturation
After infusion of endotoxin significantly higher arterial plasma lactate concentrations were observed from t = 1 to t = 10 h, reaching a maximum after 1 h of 2.5 ± 0.5 compared with 0.9 ± 0.1 mmol/l after placebo infusion (P < 0.05, n = 8) (Fig. 5A). The lactate release (venoarterial plasma lactate difference multiplied by LBF) was stable after placebo, but increased after endotoxin (Fig. 5B). During the first 10 h, arterial oxygen saturation was for each subject at each time of measuring >97% and no significant differences in venous oxygen saturation was observed. These observations, taken together with the observed increase in LBF, indicate that changes in blood lactate concentrations were not associated with reduced tissue oxygen supply. Moreover, the increase in plasma lactate was associated with a significant increase in plasma pH from 7.39 ± 0.01 to a maximum of 7.43 ± 0.01 (P < 0.05, n = 8) at t = 5 h, whereas no changes were seen after placebo infusion. The increase in pH may have been related in part to hyperventilation because a decrease in PCO2 after endotoxin infusion was seen, reaching a nadir at t = 5 h of 4.7 ± 0.1 compared with 5.3 ± 0.1 kPa (P < 0.05, n = 7-8) after placebo.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that in healthy humans endotoxemia leads to hypokalemia and a relative accumulation of K+ in the legs associated with increases in plasma catecholamines and plasma lactate concentrations without hypoxia, signs of hypoperfusion or reduced pH. In this model, endotoxin induced clinical, hemodynamic, immunologic, and hormonal responses resembling the responses seen in patients with sepsis, which ensures clinical relevance of the obtained results.
In endotoxic rats, an increase in the activity of the pool of skeletal
muscle Na+-K+ pumps has been shown without an
associated increase in expression of messenger RNA for the - or the
-subunits of the pump or increasing Na+-K+
pump number (22). Thus the present study supports the
hypothesis that endotoxin exposure increases skeletal muscle
Na+-K+-ATPase activity (13) as
assessed by a significant decrease in plasma K+ and a
relative increase in K+ uptake in the leg induced by
increased levels of catecholamines. The present observation of
hypokalemia after endotoxin exposure has previously been observed in
cows (23). We observed a constant loss of K+
from the muscles in the placebo group. This is in accordance with
previous studies in humans showing that at rest venous plasma K+ is higher than arterial plasma K+ (6,
9, 15, 17, 27). This may be explained by clearance of
K+ into the muscles for buffering after a meal, followed by
a gradual loss of K+ back to the extracellular fluid volume
(ECV) and eventually excretion by the kidneys. After endotoxin
infusion the plasma lactate level remained elevated after maximum
changes in the K+ homeostasis and in plasma epinephrine
level were seen (Fig. 5A). This observation most likely
reflects the variability in the measurements of plasma lactate as also
seen in Fig. 5B, but may also reflect that plasma
epinephrine level did not completely reach control level during this
period (Fig. 2). However, a highly significant increase in plasma
lactate of up to 177% was induced by endotoxin and it is of interest
that this increase was of same order of magnitude as the
insulin-induced ouabain-suppressible increase of 135% observed in
humans during stimulation of skeletal muscle Na+-K+-ATPase by an euglycemic-hyperinsulinemic
clamp (21). However, it should be noted that in the
present study neither the plasma lactate increase, nor the plasma
K+ decrease, was due to an insulin-induced
Na+-K+-ATPase stimulation because no
significant differences in plasma insulin concentrations were observed
after endotoxin infusion compared with placebo. The presently observed
indications of increased skeletal muscle
Na+-K+-ATPase activity during endotoxemia are
at variance with a report of no difference in cellular 86Rb
uptake in soleus muscle from rats treated with Salmonella
enteritidis endotoxin (16). However, the soleus
muscles were examined after excision and incubation in endotoxin-free
buffers. Therefore, an ongoing effect of endotoxin could not be
expected. This illustrates one of the possible pitfalls in in vitro
assays compared with in vivo studies.
Assuming a total body skeletal muscle weight of ~40% of body weight, a skeletal muscle mass in one leg drained by the femoral vein of 10% of body weight (20) and a skeletal muscle K+ content of ~75% of total body K+ content of ~3,500 mmol (3) the accumulated difference in leg K+ content in each leg 6 h after endotoxin and placebo infusions of ~9 mmol, corresponds to ~1 mmol/kg K+ skeletal muscle, i.e., 1.2%. Furthermore, assuming similar skeletal muscle K+ accumulation throughout the body, a total body skeletal muscle K+ accumulation of ~35 mmol at t = 6 h can be calculated after endotoxin infusion compared with after placebo infusion. The magnitude of this relative increase in skeletal muscle K+ cannot fully be explained by the simultaneous decline in total ECV K+ of 8 mmol [ECV (20% of body wt) × plasma K+ decrease (~0.5 mmol)]. This indicates that the K+ changes were to a certain extent the result of K+ shifts between ECV and skeletal muscles, but other organs, or regulatory mechanisms, e.g., temporal changes in renal K+ excretion, may also have been involved. After the plasma K+ nadir at t = 5 h, a gradual increase in plasma K+ was observed with an increased venoarterial K+ difference compared with before the nadir was reached (Fig. 3A). This indicates that the relative skeletal muscle K+ accumulation ceased at t = 5-6 h and was followed by an increased loss of K+ to the extracellular phase. Thus as presently as well as previously seen (18) the major effects of a single endotoxin bolus seems to vanish after ~5 h. Thus the study shows the initial effects of endotoxin on the extrarenal K+ homeostasis, but the study design does not allow further assessment of the clinical situation with the septic patient with ongoing endotoxin production. It is important to notice that the shivering observed during the increase in temperature represents muscle work. During muscle work, the excitation-contraction sequence leads to a net loss of K+ to the extracellular space (26). Thus shivering per se would have been expected to increase plasma K+. In contrast, we observed a decline in plasma K+, which can be explained by the catecholamine-induced stimulation of the Na+-K+-ATPase activity. It was ensured that the plasma K+ increase after the nadir at t = 5 h was not a result of rhabdomyolysis as indicated by unaltered plasma myoglobin concentrations.
To the best of our knowledge, the observed significant increase in renal K+ excretion has not previously been reported. It should be noted that the higher K+ excretion after endotoxin infusion was measured for the 24-h period after the infusions, whereas the skeletal muscle K+ content changes were assessed after the initial 6 h. The combination of a reduction in skeletal muscle K+ loss and an increase in renal K+ excretion would be expected to reduce plasma K+ or involve K+ loss from other compartments or organs. However, it should be stressed that during the period of increased renal K+ excretion (t = 0-24 h) skeletal muscle K+ underwent a biphasic change: first, a relative accumulation, followed by an increased K+ loss and at t = 24 h, skeletal muscle K+ may actually have been reduced after endotoxin infusion compared with placebo. This suggestion is supported by the observation of a tendency to lower plasma K+ concentrations at t = 24-32 h after endotoxin infusion.
Catecholamine stimulation of proximal tubule -adrenoceptor
increases Na+-K+-ATPase activity, whereas
a decrease is obtained by -adrenoceptor stimulation and dual
stimulation may counterbalance each other (11). A
micropuncture study showed that epinephrine reduces renal
K+ excretion (4) and a study using isolated
kidneys showed that norepinephrine also reduces K+
excretion (1). Thus it is most likely that the presently
observed increase in renal K+ excretion after endotoxin
infusion may have been the combined outcome of a reduced renal
K+ excretion due to increased levels of catecholamines but
at the same time an increased excretion induced by increased ACTH and cortisol concentration levels.
In vitro studies have shown that endotoxin via increased levels of IL-6
and TNF- reduce hepatocyte (7, 8, 28) and thyroid cell
(24) Na+-K+-ATPase activity,
respectively. Such changes would tend to increase plasma
K+. Moreover, these results indicate that the numerous
responses seen in sepsis, i.e., inflammatory, hormonal, metabolic, and
hemodynamic changes may induce different or even opposite changes in
different organs.
Taken together, the present study supports the hypothesis that in humans blood lactate level may increase under aerobic conditions. The combination of the well-known stimulatory effect on skeletal muscle Na+-K+-ATPase activity of catecholamines and the present confirmation of the correspondingly expected Na+-K+-ATPase-induced decline in plasma K+-suggests that the increase in skeletal muscle lactate release was due to increased Na+-K+-ATPase activity. The findings also point to the importance of the K+ homeostasis. It should be noted that the presently observed effect on the K+ homeostasis is not supposed to be a specific response to endotoxemia, but may be present in general in acutely and severely ill patients with a stress response. The present study indicates that in such patients hypokalemia may not necessarily be interpreted as K+ deficiency, as it may reflect (temporarily) increased muscle K+ uptake, but on the other hand it is important to compensate for an increased renal K+ excretion.
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ACKNOWLEDGEMENTS |
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We thank consulting biostatistician Gordon Doig (Royal North Shore Hospital, St. Leonards, Sydney, Australia) for valuable statistical assistance.
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FOOTNOTES |
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The study was supported in part by the Emil C. and Inger Hertz Foundation.
Address for reprint requests and other correspondence: H. Bundgaard, Royal North Shore Hospital, Main Bldg., Level 6, Dept. of Cardiology, St. Leonards, Sydney 2065 NSW, Australia (E-mail: HenningBundgaard{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.
First published November 21, 2002;10.1152/ajpheart.00639.2002
Received 23 July 2002; accepted in final form 15 November 2002.
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REFERENCES |
|---|
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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|---|
1.
Baines, AD,
and
Ho P.
Specific 1-, 2-, and -responses to norepinephrine in pyruvate-perfused rat kidneys.
Am J Physiol Renal Fluid Electrolyte Physiol
252:
F170-F176,
1987
2.
Clausen, T.
Long- and short-term regulation of the Na+-K+ pump in skeletal muscle.
News Physiol Sci
11:
24-30,
1996
3.
DeFronzo, RA,
and
Bia M.
Extrarenal potassium homeostasis.
In: The Kidney: Physiology and Pathophysiology, edited by Seldin DW,
and Giebisch G.. New York: Raven, 1985, p. 1179-1206.
4.
DeFronzo, RA,
Stanton B,
Klein-Robbenhaar G,
and
Giebisch G.
Inhibitory effect of epinephrine on renal potassium secretion: a micropuncture study.
Am J Physiol Renal Fluid Electrolyte Physiol
245:
F303-F311,
1983
5.
Elisaf, M,
Theodorou J,
Pappas H,
and
Siamopoulos KC.
Acid-base and electrolyte abnormalities in febrile patients with bacteraemia.
Eur J Med
2:
404-407,
1993[Medline].
6.
Ford, GA,
Dachman WD,
Blaschke TF,
and
Hoffman BB.
Effect of aging on 2-adrenergic receptor-stimulated flux of K+, PO4, FFA, and glycerol in human forearms.
J Appl Physiol
78:
172-178,
1995
7.
Green, RM,
Beier D,
and
Gollan JL.
Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.
Gastroenterology
111:
193-198,
1996[ISI][Medline].
8.
Green, RM,
Whiting JF,
Rosenbluth AB,
Beier D,
and
Gollan JL.
Interleukin-6 inhibits hepatocyte taurocholate uptake and sodium-potassium-adenosinetriphosphatase activity.
Am J Physiol Gastrointest Liver Physiol
267:
G1094-G1100,
1994
9.
Green, S,
Langberg H,
Skovgaard D,
Bulow J,
and
Kjaer M.
Interstitial and arterial-venous [K+] in human calf muscle during dynamic exercise: effect of ischaemia and relation to muscle pain.
J Physiol
529:
849-861,
2000
10.
Hallman, H,
Farnebo LO,
Hamberger B,
and
Johnsson G.
A sensitive method for the determination of plasma catecholamines using liquid chromatography with electrochemical detection.
Life Sci
23:
1049-1052,
1978[ISI][Medline].
11.
Holtback, U,
and
Eklof AC.
Mechanism of FK 506/520 action on rat renal proximal tubular Na+,K+-ATPase activity.
Kidney Int
56:
1014-1021,
1999[ISI][Medline].
12.
James, JH,
Fang CH,
Schrantz SJ,
Hasselgren PO,
Paul RJ,
and
Fischer JE.
Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis.
J Clin Invest
98:
2388-2397,
1996[ISI][Medline].
13.
James, JH,
Luchette FA,
McCarter FD,
and
Fischer JE.
Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis.
Lancet
354:
505-508,
1999[ISI][Medline].
14.
James, JH,
Wagner KR,
King JK,
Leffler RE,
Upputuri RK,
Balasubramaniam A,
Friend LA,
Shelly DA,
Paul RJ,
and
Fischer JE.
Stimulation of both aerobic glycolysis and Na+-K+-ATPase activity in skeletal muscle by epinephrine or amylin.
Am J Physiol Endocrinol Metab
277:
E176-E186,
1999
15.
Juel, C,
Bangsbo J,
Graham T,
and
Saltin B.
Lactate and potassium fluxes from human skeletal muscle during and after intense, dynamic, knee extensor exercise.
Acta Physiol Scand
140:
147-159,
1990[ISI][Medline].
16.
Karlstad, MD,
and
Sayeed MM.
Effect of endotoxic shock on basal and insulin-mediated Na+/K+-pump activity in rat soleus muscle.
Circ Shock
38:
222-227,
1992[Medline].
17.
Katz, A,
Sahlin K,
and
Juhlin-Dannfelt A.
Effect of -adrenoceptor blockade on H+ and K+ flux in exercising humans.
J Appl Physiol
59:
336-341,
1985
18.
Krabbe, KS,
Bruunsgaard H,
Hansen CM,
Moller K,
Fonsmark L,
Qvist J,
Madsen PL,
Kronborg G,
Andersen HO,
Skinhoj P,
and
Pedersen BK.
Ageing is associated with a prolonged fever response in human endotoxemia.
Clin Diagn Lab Immunol
8:
333-338,
2001
19.
Madias, JE,
Shah B,
Chintalapally G,
Chalavarya G,
and
Madias NE.
Admission serum potassium in patients with acute myocardial infarction: its correlates and value as a determinant of in-hospital outcome.
Chest
118:
904-913,
2000
20.
Medbo, JI,
Hanem S,
Noddeland H,
and
Jebens E.
Arterio-venous differences of blood acid-base status and plasma sodium caused by intense bicycling.
Acta Physiol Scand
168:
311-326,
2000[ISI][Medline].
21.
Novel-Chate, V,
Rey V,
Chiolero R,
Schneiter P,
Leverve X,
Jequier E,
and
Tappy L.
Role of Na+-K+-ATPase in insulin-induced lactate release by skeletal muscle.
Am J Physiol Endocrinol Metab
280:
E296-E300,
2001
22.
O'Brien, WJ,
Lingrel JB,
Fischer JE,
and
Hasselgren PO.
Sepsis increases skeletal muscle sodium, potassium-adenosinetriphosphatase activity without affecting messenger RNA or protein levels.
J Am Coll Surg
183:
471-479,
1996[Medline].
23.
Ohtsuka, H,
Ohki K,
Tajima M,
Yoshino T,
and
Takahashi K.
Evaluation of blood acid-base balance after experimental administration of endotoxin in adult cow.
J Vet Med Sci
59:
483-485,
1997[Medline].
24.
Pekary, AE,
Levin SR,
Johnson DG,
Berg L,
and
Hershman JM.
Tumor necrosis factor- (TNF-) and transforming growth factor-1 (TGF-1) inhibit the expression and activity of Na+/K+-ATPase in FRTL-5 rat thyroid cells.
J Interferon Cytokine Res
17:
185-195,
1997[ISI][Medline].
25.
Radegran, G.
Ultrasound Doppler estimates of femoral artery blood flow during dynamic knee extensor exercise in humans.
J Appl Physiol
83:
1383-1388,
1997
26.
Schmidt, TA,
Bundgaard H,
Olesen HL,
Secher NH,
and
Kjeldsen K.
Digoxin affects potassium homeostasis during exercise in patients with heart failure.
Cardiovasc Res
29:
506-511,
1995[ISI][Medline].
27.
Sjogaard, G,
Adams RP,
and
Saltin B.
Water and ion shifts in skeletal muscle of humans with intense dynamic knee extension.
Am J Physiol Regul Integr Comp Physiol
248:
R190-R196,
1985
28.
Utili, R,
Abernathy CO,
and
Zimmerman HJ.
Inhibition of Na+, K+-adenosinetriphosphatase by endotoxin: a possible mechanism for endotoxin-induced cholestasis.
J Infect Dis
136:
583-587,
1977[Medline].
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0-9 h of arteriovenous plasma
K+ difference times leg plasma flow. The difference between
accumulated K+ after infusion of endotoxin and accumulated
K+ after infusion of placebo is indicated (endotoxin
placebo). Statistics: with the use of two-way RM ANOVA (see
MATERIALS AND METHODS) the level of accumulated
K+ was found to be statistically significantly increased
after endotoxin compared with placebo. Values are means ± SE.
