INVITED REVIEW
Skeletal muscle regulates extracellular potassium
Alicia A.
McDonough,
Curtis B.
Thompson, and
Jang H.
Youn
Department of Physiology and Biophysics, University of
Southern California Keck School of Medicine, Los Angeles,
California 90089-9142
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ABSTRACT |
Maintaining extracellular fluid
(ECF) K+ concentration ([K+]) within a narrow
range is accomplished by the concerted responses of the kidney, which
matches K+ excretion to K+ intake, and skeletal
muscle, the main intracellular fluid (ICF) store of K+,
which can rapidly buffer ECF [K+]. In both systems,
homologous P-type ATPase isoforms are key effectors of this
homeostasis. During dietary K+ deprivation, these P-type
ATPases are regulated in opposite directions: increased abundance of
the H,K-ATPase "colonic" isoform in the renal collecting duct
drives active K+ conservation while decreased abundance of
the plasma membrane Na,K-ATPase
2-isoform leads to the
specific shift of K+ from muscle ICF to ECF. The
skeletal muscle response is isoform and muscle specific:
2 and
2, not
1 and
1, levels are depressed, and fast glycolytic muscles
lose >90%
2, whereas slow oxidative muscles lose
~50%; however, both muscle types have the same fall in cellular
[K+]. To understand the physiological impact, we
developed the "K+ clamp" to assess insulin-stimulated
cellular K+ uptake in vivo in the conscious rat by
measuring the exogenous K+ infusion rate needed to maintain
constant plasma [K+] during insulin infusion. Using the
K+ clamp, we established that K+
deprivation leads to near-complete insulin resistance of cellular K+ uptake and that this insulin resistance can occur
before any decrease in plasma [K+] or muscle
Na+ pump expression. These studies establish the advantage
of combining molecular analyses of P-type ATPase expression with in
vivo analyses of cellular K+ uptake and excretion to
determine mechanisms in models of disrupted K+ homeostasis.
sodium, potassium-adenosine triphosphatase; hydrogen,
potassium-adenosine triphosphatase; potassium clamp; hypokalemia; ion
homeostasis
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INTRODUCTION |
RECENT CLINICAL STUDIES HAVE
demonstrated a positive association between diets rich in
K+ and the control of blood pressure and prevention of
stroke (4, 6, 17). This association is not surprising
given the fundamental importance of K+ (the main
intracellular cation) in determining cell volume as well as nerve and
muscle excitability, both dependent on the steep transmembrane
K+ gradient established by the ubiquitous Na+
pump, Na,K-ATPase. The hydrolysis of ATP by the Na+ pump
fuels the coupled uphill transport of K+ into the cell and
Na+ out of the cell. Extracellular K+
concentration ([K+]) is closely regulated, between 3.8 and 5 mM, by the concerted responses of two organ systems: muscle,
which contains the major pool of K+ and regulates
K+ distribution between the ICF and ECF compartments, and
kidneys, which regulate K+ excretion by secreting or
actively reabsorbing K+ (Fig.
1) (12, 13, 18). The duet
between these two systems is critical for both short-term and long-term
K+ homeostasis.

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Fig. 1.
K+ homeostasis in an average person.
Extracellular fluid (ECF) K+ homeostasis is maintained by
concerted regulation of kidney and muscle. ECF K+
continually enters the kidneys as a function of glomerular filtration
rate (GFR), and renal adjustments match K+ output to
K+ input: normally 90% of the filtered load is reabsorbed.
During K+ deprivation or fasting, nearly 100% of the
filtered load is reabsorbed. Skeletal muscle takes up excess
K+ from the ECF after a meal, driven by insulin, and also
takes up excess ECF K+ during exercise, driven by
catecholamines. Skeletal muscle continually loses muscle intracellular
fluid (ICF) K+ to the ECF with muscle activity. During
K+ deprivation, the loss of ICF K+ to the ECF
is increased because the cellular uptake of K+ is
decreased, buffering the fall in ECF K+ concentration
([K+]).
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To frame the challenges to K+ homeostasis, one can consider
commonly encountered challenges that require an acute response. Total
extracellular K+ is ~70 meq, and the average dietary
K+ load is 80 meq/day (greater than the total ECF
K+) (Fig. 1). Consider the consequences of eating an
average cantaloupe, which contains ~2 g or 50 meq of K+
(50) that could be added to the ECF within a very short
time of its ingestion. If not adjusted quickly by renal excretion or muscle uptake, ECF [K+] would increase to a dangerous 7.5 mM. However, consuming the melon increases blood glucose and stimulates
insulin release, which causes muscle and fat to actively take up not
only glucose but also excess K+ not excreted in the short
term by the kidneys. Muscle activity releases K+
chronically into the ECF and, mysteriously, the appropriate fraction is
excreted by the kidneys rather than taken up again by the muscles; thus
renal output is adjusted to match dietary input. As another example,
one can consider K+ balance during vigorous exercise by
which K+ release exceeds the capacity for muscle to
actively take it up again, and muscle ECF [K+] increases
within minutes by >3 mM (12, 13). In this case, nerve
excitation and consequent release of catecholamine stimulate active
K+ uptake into muscle via the Na,K-ATPase to restore ECF
[K+] (1, 12, 13). Another example occurs
when there is too much ECF [K+] during end-stage renal
disease, where K+ output is effected by periodic dialysis,
and dietary K+ must be sequestered in the muscle between
dialysis sessions. On the occasions when life-threatening hyperkalemia
develops, the therapy is acute administration of both insulin and
adrenergic agonists to maximize muscle K+ uptake
(1).
Complementing these examples of acute regulation, chronic adjustments
must be activated when K+ intake is continuously less than
output, delaying and minimizing the resulting hypokalemia (lists of
causes of hypokalemia can be found in any renal physiology text). When
hypokalemia results from fasting or consuming K+-deficient
diets, the kidney avidly retains K+ by shifting from net
K+ secretion to net K+ absorption via the
apical H,K-ATPases in the distal nephron, and renal output falls to
near zero (18, 51). However, K+ loss in the
stools and sweat persists, so K+ must be continuously
redistributed from muscle stores to the ECF, with the end result that
muscle cell [K+] falls to balance the discrepancy between
K+ input and output over time (20, 37, 48). A
remarkable challenge to K+ homeostasis was documented in a
study of soldiers in summertime basic training, who lost >40 meq
K+/day in sweat alone. High muscle activity shifted plenty
of K+ into the ECF so that frank hypokalemia did not
develop, but after 11 days of training there was a total body
K+ deficit of >400 meq. This was attributable to the fact
that, besides sweat loss, K+ loss in urine persisted
because daily bouts of dehydration stimulated aldosterone secretion
(25).
Active transport of K+ by muscle Na,K-ATPase plays a
central role in these scenarios of acute and chronic challenges to
K+ homeostasis. This review will focus on the molecular
mechanisms in place in muscle that contribute to K+
homeostasis, in particular, muscle-specific regulation of
Na+ pump isoforms, and a novel method we developed to
assess cellular K+ uptake in vivo.
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P-TYPE ATPases AND K+ HOMEOSTASIS |
As introduced above, adjustments to maintain K+
homeostasis are effected by a tight control of the activity and
abundance of genetically related P-type ATPases: the muscle
Na+ pumps (Na,K-ATPase) actively transport K+
from ECF into muscle, and the renal H+/K+ pumps
(H,K-ATPase) actively reabsorb K+ from the renal tubular
fluid back into the ECF during K+- deficient states
(45, 47). Both Na,K-ATPase and H,K-ATPase are 1:1
heteromers of ~100 kDa
-catalytic subunits and ~50 kDa
-glycoprotein subunits. These classes of P-type ATPases share 65%
homology, and there are multiple isoforms of each type of pump
(24, 45, 47).
The existence of isoforms suggests the potential for differential
expression, function, and regulation. Indeed, isoform- and tissue-specific regulation of these pumps during challenges to K+ homeostasis provides the compelling rationale for the
existence of these isoforms. In the kidney, both gastric and nongastric isoforms of the H,K-ATPase are found in the distal portion of the
nephron (24, 45). Recent reviews have focused on the renal control of K+ excretion (18, 45, 51), and
specifically on H,K-ATPases (24, 45). K+
output is ultimately controlled in the collecting tubules and duct,
where, during K+ restriction, there are increased abundance
and activity of the nongastric, colonic isoform of the
-subunit of
H,K-ATPase along with the
1- isoform classically
assigned to the Na+ pump (
c
1)
in apical membranes (15, 16, 26, 27) as well as decreased
abundance of the ROMK secretory K+ channel
(36) (Fig. 2). These
responses are responsible, at least in part, for the shift from
K+ secretion to active K+ reabsorption that
occurs in the collecting duct during K+-restricted states.
Studies in colonic H,K-ATPase-deficient mice suggest that the decrease
in K+ secretion may be a very important component, as these
mice are able to reduce urinary K+ excretion during
K+ deprivation to nearly the same extent as mice
with normal H,K-ATPase levels (35). The remainder of
this review will focus on the role of muscle in K+
homeostasis.

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Fig. 2.
Compartmental model of K+ homeostasis. Input
and output routes between ICF, ECF, and the animal's exterior are
illustrated. Red oxidative muscle fibers express plasma membrane
Na+ pumps (Na,K-ATPase) composed of either
1- or 2-catalytic subunits along with
1-glycoprotein subunits, and
2 1 pumps are found in endosomal vesicles.
White glycolytic muscle fibers express either 1- or
2- along with 2-glycoprotein subunits;
there is as yet no evidence for endosomal pools. A number of
K+ channels mediate K+ efflux from the skeletal
muscle (down arrow). ECF is filtered into the renal tubule fluid by
glomerular filtration. All along the nephron, basolateral Na,K-ATPase
brings K+ into the renal ICF. In collecting duct principal
cells, apical ROMK K+ channels secrete K+ into
tubule fluid. Collecting duct intercalated cells express apical
H,K-ATPase, and the colonic isoform ( c 1)
is increased during K+ deprivation to increase active
K+ reabsorption.
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With regard to Na+ pump isoforms, presently four
-isoforms have been identified:
1 is fairly
ubiquitous, whereas
2,
3, and
4 have a limited tissue-specific expression pattern.
Relevant to this review, both
1 and
2 are
major isoforms in adult skeletal muscle and have ~92% homology,
whereas
3 and
4 are not appreciably expressed. There are also three isoforms of the
-glycoprotein:
1 is expressed in most tissues,
2 and
3 have a more restricted distribution, and
1 and
2 are expressed in muscle. Specific characteristics of Na+ pump isoform structure and function
have been recently reviewed (7, 47).
Skeletal muscle is composed of a heterogeneous mix of muscle fiber
types (46) historically classified by their metabolic (oxidative vs. glycolytic), contractile (fast twitch vs. slow twitch),
and/or phenotypic (red vs. white) properties. Although most muscles
contain a mixture of muscle fiber types, at the phenotypic extremes
soleus contains 87% slow oxidative red fibers that are important for
antigravity, weight bearing, and sustained movement, whereas white
gastrocnemius contains 84% fast glycolytic white fibers important for
concentrated bursts of power (2, 3). Studies in muscles at
the phenotypic extremes have helped to determine whether there is a
functional division of labor between muscle types, while providing
information requisite to interpret function and response in mixed-fiber
muscles. To understand the complexity of muscle-specific isoform
expression, we assayed
1,
2,
1, and
2 abundance in a panel of five
phenotypically distinct muscles by immunoblot analysis and found that,
indeed, there are distinct distributions of Na+ pump
-
and
-isoforms in muscle. Expression of
2 was fairly uniform across control muscles, but
1 expression was
twice as high in oxidative muscles such as soleus and diaphragm than in mixed or fast glycolytic muscles such as gastrocnemius and extensor digitorum longus (49). It is difficult to assess the
fraction of
1- and
2-type pumps in
muscle, but estimates place the percentage of
2 protein
at 40-60% (28, 48). The Klip (23) and
McDonough (49) laboratories have also found that
1 is expressed without
2 in soleus and
diaphragm and
2 is expressed without
1 in
white gastrocnemius (23, 49). Thus the predominant
isoforms in rat red oxidative muscle are
1
1 and
2
1
and in white glycolytic muscle are
1
2-and
2
2-isoforms (Fig. 2); both are expressed in mixed-fiber muscles. This differential expression suggests the
possibility for differential subcellular distribution or regulation. Indeed,
2
1-type Na+ pumps are
also located in internal endosomal vesicle membranes in red, but not
white, muscle (22) (Fig. 2), and insulin provokes a
redistribution from internal membranes to the surface (29) in red muscle, which can explain, at least in part, insulin stimulation of active K+ uptake.
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REGULATION OF MUSCLE Na,K-ATPase DURING
K+ DEPRIVATION |
Skeletal muscle has an altruistic specialization to lose
K+ in the face of whole body K+ deprivation to
preserve ECF [K+]. This response is the converse of that
observed in cultured cells. When muscle, heart, or kidney cells are
placed in low-K+ medium, the drop in extracellular
[K+] increases the gradient for K+ loss from
the cells and limits Na,K-ATPase activity, leading to both a fall in
ICF K+ and a reciprocal rise in ICF Na+. These
stimuli provoke an increase in Na+ pump synthesis and a
subsequent increase in the number of active Na+ pumps at
the plasma membrane, which counteracts the increased K+
leak from the cells (8, 30, 39, 52). In cultured kidney cells, the increase in Na+ pump abundance is driven by an
increase in
1 (not
1) mRNA levels, which
allows an increase in the synthesis and/or accumulation of
1
1 heteromers (30-32).
We also detected an 11-fold increase in
1 protein levels
(with a 3-fold increase in
1) in the outer medulla of
rats deprived of K+ for 14 days and postulated that the
increased pool of
1 may play a critical role in driving
assembly and accumulation of H,K-ATPase induced during K+
deprivation through
C
1 heteromer
formation (34) (Fig. 2). An increase in Na+
pump number is also seen in erythrocytes of hypokalemic animals, which
maintain normal ICF levels of Na+ and K+
(reviewed in Ref. 13). The response is just the opposite
in skeletal muscle in vivo, the main stores of the body's
K+. Muscle loses cell [K+] during
K+ deprivation and responds by decreasing Na+
pump number, which facilitates further loss of cell K+ to
the ECF, which buffers the fall in ECF [K+] (20,
37). Other tissues such as liver and brain do not lose cell
K+ during hypokalemia (20, 37). Thus the
response of skeletal muscle to K+ deprivation must be
studied in vivo rather than in cultured muscle cells.
Insight into the molecular mechanisms responsible for the loss of
muscle K+ during K+ deprivation was provided 20 years ago by Norgaard et al. (37). In this comprehensive
study, they established that rats fed a K+-deficient diet
for 2 wk had a 40% decrease in ICF [K+] in
gastrocnemius, a decrease in K+ influx into isolated soleus
(by 86Rb uptake), and a >50% decrease in Na+
pump activity along with a similar decrease in Na+ pump
number measured in intact soleus muscle by the binding of 3H-labeled ouabain, a specific inhibitor of Na,K-ATPase.
This work preceded the cloning and identification of Na+
pump isoforms, and it was subsequently established that the
1-isoform is quite ouabain resistant in rodents,
so the decrease in ouabain binding likely reflects a change in the
2-isoform abundance (38). Because ouabain
binding measurements were conducted in intact muscles, the measurement
reflects decreased active
2-type pumps in the surface
membranes. This could arise from redistribution of pumps to internal
stores, inhibition of pumps in the plasma membrane, or a change in
total abundance of pumps (Fig. 3).
Whether there is also a change in the
1-isoform could
not be assessed by ouabain binding.

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Fig. 3.
Biosynthesis and regulation of Na+ pump
isoforms during low-K+ diet. Top: schematic of
parallel synthesis of Na,K-ATPase - and -subunits, assembly in
the endoplasmic reticulum (ER), and processing and targeting to the
plasma membrane. Potential mechanisms of regulation of mature
Na+ pump activity or abundance in the plasma membrane are
shown [increase ( ) and decrease ( )].
Bottom: results of 10 days (10d) of a low-K+
diet on 2 and 2 mRNA and protein levels
in gastrocnemius (49). Each lane represents a sample from
a different animal, and a constant amount of protein or total RNA was
applied to each lane. Samples were deglycosylated, which significantly
improves immunodetection and quantitation of the heavily glycosylated
-subunits.
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These findings stimulated us to examine whether the decrease in muscle
Na+ pumps in the K+-deprived muscle was isoform
specific. The results established an isoform and muscle specificity of
the response to 10-day dietary K+ deprivation: the levels
of the ubiquitous
1-isoform were unchanged, whereas
2 decreased 30% in diaphragm, 60% in soleus, and
>90% in white gastrocnemius; and
1 was decreased
minimally (20% fall in soleus), whereas
2 decreased
75% in white gastrocnemius (5, 48, 49). Surprisingly,
and
mRNA levels were unchanged during 2-10 days of a
K+-deficient diet (48) (Fig. 3). Despite these
differences, the associated fall in cell [K+] was similar
in both soleus and white gastrocnemius (~20 mM), suggesting that
other factors besides 
-pool sizes (e.g., redistribution from
surface or inhibition in soleus) may be important to the response
(5, 48, 49). Taken together, the results of these studies
demonstrate that the expression of the muscle
2 (not
1)- and
2 (perhaps
1)-subunits are specifically depressed during K+ deprivation and hypokalemia in vivo mediated by
decreased synthesis rate or increased degradation rate of the subunits.
The findings are in distinct contrast to those in cultured cells
deprived of K+, in which an increase in Na,K-ATPase
1 synthesis drives the assembly of additional
1
1 pumps, which facilitates
K+ accumulation. These in vivo results provide evidence
that the presence and regulation of the
2-isoform in
skeletal muscle provided the evolutionary advantage needed by complex
organisms to maintain transmembrane K+ gradients in the
face of fluctuations in K+ availability (33).
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THE "K+ CLAMP" TO MEASURE IN VIVO CELLULAR
K+ UPTAKE |
The findings in K+-deprived rats support the
hypothesis that a decrease in active K+ uptake by
Na,K-ATPase
2 leads to a net loss of K+ from
muscle and transfer to ECF, where it buffers the fall in [K+]. To establish a physiological link in vivo between
the fall in muscle
2 Na+ pump expression and
a decrease in active K+ uptake, we exploited the theory
behind the "glucose-clamp" technique, used to measure
insulin-stimulated glucose uptake in vivo, to develop a
K+ clamp to measure insulin-activated K+
uptake. In brief, conscious rats are infused with insulin to stimulate
K+ (and glucose) uptake, and then, based on rapid and
frequent assays of plasma [K+], infused with enough
K+ (and glucose) to clamp plasma K+ (and
glucose) at baseline (Fig. 4,
A and B). The total amount of K+
infused (Kinf) over a defined time period is equivalent to
the sum of the insulin-stimulated portions of cellular K+
uptake and K+ excretion (11). Previous studies
by us (11) and others (44) showed that
insulin at physiological concentrations does not significantly increase
renal K+ excretion. Therefore, most of Kinf
should be attributable to insulin-stimulated cellular K+
uptake. Thus the K+ infusion rate during the K+
clamp appears to be a good measure of insulin-stimulated cellular K+ uptake.

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Fig. 4.
The K+ clamp. A: illustration of the method
as described in Choi et al. (11). B:
hyperinsulinemic (5 mU · kg 1 · min 1) glucose
and K+ clamps in control ( ) and 2 ( )- and 10-day (+) K+-deprived rats.
Adapted from Ref. 11.
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We tested the hypothesis that insulin-stimulated cellular
K+ uptake is a function of muscle
2
abundance by comparing uptake in rats deprived of K+ for
only 2 days, where there was a minor drop in plasma [K+ ] (from 4.2 to 3.8 mM) and muscle
2, with those deprived
of K+ for 10 days, where plasma [K+ ] fell to
2.9 mM and mixed-fiber muscle
2 decreased by 50%. Surprisingly, the results did not support the hypothesis. After 2 days
of K+ deprivation, there was an 80% reduction in
insulin-stimulated cellular K+ uptake without a significant
fall in Na,K-ATPase pool size or Na,K-ATPase enzymatic activity
measured under maximal velocity conditions in total membranes (Fig.
5), whereas insulin-stimulated glucose
infusion was unchanged (Fig. 4B). We are left to conclude that another mechanism comes into play to reduce cellular
K+ uptake before the Na+ pump
2
pool size falls. Possibilities include failure of insulin-induced translocation to the plasma membrane, inhibition of Na+
pump activity in the plasma membrane not detected in the assay of total
maximal Na,K-ATPase activity, activation of a K+ efflux
route, or inhibition of a K+ uptake route unrelated to
Na,K-ATPase. Ongoing studies using subcellular fractionation suggest
the first possibility, that endosomal pools of Na,K-ATPase
2 are resistant to insulin-stimulated redistribution to
the plasma membrane, whereas redistribution of GLUT4 is normal after 2 days of K+ deprivation (not shown) (19). After
10 days of a low-K+ diet, Kinf was further
reduced to only 6% of control, likely reflecting the combined effects
of resistance to insulin-stimulated redistribution and reduced pool
size of Na,K-ATPase
2 (Figs. 4B and 5). The
K+ clamp technique proved to be a very valuable tool for
analyzing the impact of molecular changes, testing hypotheses, and
predicting new hypotheses.

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Fig. 5.
Insulin-mediated plasma K+ disappearance
(K ), Na,K-ATPase 2-subunit
abundance, assessed by immunoblot of a constant amount of homogenate
protein, and Na,K-ATPase activity in mixed fiber tibialis anterior
muscles of control (day 0) rats and rats fed a
K+- deficient diet for 2 or 10 days. Adapted from Ref.
11.
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WHAT "ERROR SIGNAL" DRIVES CHANGES IN K+
TRANSPORT? |
The homeostatic regulation of K+ during
insufficient K+ intake is often viewed as a simple
negative-feedback system: as plasma K+ falls, the kidneys
react by actively reabsorbing filtered K+ to minimize
further K+ loss, while skeletal muscle releases cell
K+, as a consequence of decreased active K+
uptake, to buffer the restore falling K+ (12, 13, 40a). Although this proposed feedback suggests a causal role for
plasma K+ as the error signal that drives the
responses, there is evidence that regulatory responses precede changes
in plasma [K+ ]. We discovered, inadvertently, that when
rats were fed a high-fat diet (to induce resistance to
insulin-stimulated glucose uptake), dietary K+ intake was
reduced to one-third of normal (10). This regime decreased
urinary K+ excretion as well as insulin-stimulated cellular
K+ uptake (in addition to the decrease in
insulin-stimulated glucose uptake), both of which were restored
when dietary K+ was matched to that of controls.
Interestingly, there was a strong correlation between urinary
K+ excretion and insulin-stimulated cellular K+
uptake, suggesting the possibility that the kidneys' function to
excrete K+ and insulin's action to promote cellular
K+ uptake are similarly (in concert) regulated in response
to K+ intake. Importantly, basal plasma [K+]
was not reduced at all by the threefold lower K+
intake, indicating the existence of an effective homeostatic mechanism.
These data suggest that the body must have a way of sensing
low-K+ intake independently of plasma K+.
A number of laboratories have investigated the sensing of
K+ status. Muscle adaptation to K+ deprivation
is apparently not dependent on the nervous system, as the Clausen
laboratory (14) established that there was the same
ultimate loss of ouabain binding sites during K+
deprivation in control and denervated muscles. Rabinowitz and colleagues (40, 42) theorized that K+ sensors
in the gut, portal circulation, and/or liver respond to local changes
in K+, secondarily to enteric changes. In sheep, they
demonstrated that urinary K+ excretion increased after a
meal, whether or not there was a change in plasma K+, and
then progressively decreased. When sheep were fasted for 1 day between
feeding days, urinary K+ fell, and, when they were refed,
K+ excretion was proportionate to the K+
content of the meal. "Meal-induced" kaliuresis did not change aldosterone, insulin, or glucagon levels, and the mediators of this
"reflex kaliuresis" remain undetermined (40-42).
The suggestion that a novel K+-sensitive receptor may exist
is not unreasonable given the identification of
Ca2+-sensing receptors found in a number of tissues
(9) and glucosensors localized to the portal vein
(21). K+-sensing receptors in the hepatic
portal vein or liver could detect changes in K+ intake but
may not respond to urinary K+ wasting provoked by diuretics
in the face of normal diet (until plasma K+ fell).
In conclusion, the studies reviewed establish the advantage and
necessity of combining molecular analyses of P-type ATPase expression
with in vivo analyses of cellular K+ uptake and excretion
for a determination of mechanisms and mediators in models of disrupted
K+ homeostasis.
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ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grants DK-57678 and DK-34316 and a
Grant-in-Aid from the American Heart Association, Western States Affiliate.
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FOOTNOTES |
Address for reprint requests and other correspondence:
A. A. McDonough, Dept. of Physiology and Biophysics, Univ.
of Southern California Keck School of Medicine, 1333 San Pablo St., Los
Angeles, CA 90089-9142 (E-mail:
mcdonoug{at}hsc.usc.edu).
10.1152/ajprenal.00360.2001
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