Potassium Physiology - Clinical Tree

Introduction

Regulation of total body potassium (K ⁺ ) ion homeostasis is vital for survival. Changes in the concentration of K ⁺ ions in plasma (P _K ) are associated with changes in the negative voltage across cell membranes and the resting membrane potential (RMP). This may have dangerous consequences (e.g., altered cardiac impulse conduction causing an arrhythmia).

Abbreviations

P _K , concentration of potassium (K ⁺ ) ions in plasma
U _K , concentration of K ⁺ ions in the urine
P _Na , concentration of sodium (Na ⁺ )ions in plasma
U _Na , concentration of Na ⁺ ions in the urine
P _Cl , concentration of chloride (Cl ⁻ ) ions in plasma
U _Cl , concentration of Cl ⁻ ions in the urine
P _HCO3 , concentration of bicarbonate (HCO ₃ ^– ) ions in plasma
P _Glucose , concentration of glucose in plasma
P _Urea , concentration of urea in plasma
P _Creatinine , concentration of creatinine in plasma
U _Creatinine , concentration of creatinine in the urine
P _Osm , osmolality in plasma
U _Osm , osmolality in the urine
CDN, cortical distal nephron, which includes the late distal convoluted tubule, connecting segment, and the cortical collecting duct
DCT, distal convoluted tubule
CCD, cortical collecting duct
RMP, resting membrane potential
P _Aldosterone , concentration of aldosterone in plasma
ECF, extracellular fluid
ICF, intracellular fluid
Na-K-ATPase, sodium-potassium- ATPase
ENaC, epithelial sodium ion channel
ADP, adenosine diphoshate
ATP, adenosine triphosphate
K _ATP , K ⁺ ion channel that is gated by intracellular nucleotides
ROMK, renal outer medullary potassium ion channel

The vast majority of K ⁺ ions in the body are located in cells. K ⁺ ions are retained in cells by an electrical force because the cell interior has a negative voltage caused by the negatively charged intracellular organic phosphates. Specific channels for K ⁺ ions in cell membranes permit K ⁺ ions to diffuse out of cells down their concentration difference. These chemical and electrical forces eventually come into balance, and an equilibrium potential for K ⁺ ions is achieved if there is sufficient K ⁺ ion channel conductance in the cell membranes. Because cell membranes have much higher permeability to K ⁺ ions than to sodium (Na ⁺ ) ions, the RMP is close to the equilibrium potential for K ⁺ ions.

Regulation of K ⁺ ion homeostasis has two main aspects: (1) control of the transcellular distribution of K ⁺ ions, which is vital for survival because it limits acute changes in the P _K , and (2) regulation of K ⁺ ion excretion by the kidney, which maintains whole body K ⁺ ion balance; this is, however, a much slower process.

The shift of K ⁺ ions into cells requires an increase in cell interior negative voltage. This can be achieved by increasing flux via the Na-K-ATPase, which results in net export of positive charges out of cells.

The major site where the renal excretion of K ⁺ ions is regulated is in the late cortical distal nephron (CDN), namely the late distal convoluted tubule (DCT), the connecting segment, and the cortical collecting duct (CCD). Two factors influence the rate of excretion of K ⁺ ions: (1) the rate of net secretion of K ⁺ ions by principal cells in the CDN and (2) the flow rate in the terminal CDN (i.e., the number of liters of fluid that exit the terminal CCD). To gain insights into the physiology of the regulation of K ⁺ homeostasis, it is helpful to examine this process from a Paleolithic perspective. The diet consumed by our ancient ancestors consisted mainly of fruit and berries, which provided a very small amount of Na ⁺ and chloride (Cl ⁻ ) ions but episodic and at times large loads of K ⁺ ions. Hence, there was a need for mechanisms to ensure renal conservation of sodium chloride (NaCl) to avoid a hemodynamic threat. To avoid the risk of dangerous hyperkalemia and cardiac arrhythmia, there was a need to have mechanisms to shift ingested K ⁺ ions rapidly into the liver before they could reach the heart and mechanisms to switch the renal response from NaCl conservation to K ⁺ ion excretion after ingested K ⁺ ions are released from liver cells.

It is important to realize that hyperkalemia and hypokalemia are not specific diseases; rather, they are the result of many disorders with different underlying pathophysiology. Therefore, an understanding of the physiology of K ⁺ ion homeostasis is critical to determine the underlying pathophysiology of each disorder and the appropriate therapy.

Objectives

▪
To illustrate the common strategy used to control movement of K ⁺ ions across cell membranes. This requires a driving force (i.e., a more negative voltage in the area where K ⁺ ions must be retained) and regulation of the number of open K ⁺ channels in cell membranes.
▪
To illustrate how the voltage across cell membranes is regulated and its implications for the control of the shift of K ⁺ ions into cells.
▪
To illustrate how excretion of K ⁺ ions by the kidneys is regulated to maintain overall balance for K ⁺ ions.
▪
To illustrate that examining this process from a Paleolithic perspective provides insights into the control of K ⁺ ion homeostasis.

Case 13-1: Why Did I Become So Weak?

A very fit, active, 27-year-old Caucasian woman was in excellent health until about 1 year ago. Her past medical history revealed mild asthma, for which she took a bronchodilator on an intermittent basis. In the past year, she had three episodes of extreme weakness. Each episode lasted for about 12 hours, and she felt perfectly well between attacks. On more detailed questioning, she said that she had ingested a large amount of sugar before the first attack. Each subsequent attack, however, was not preceded by the use of a bronchodilator, performance of exercise, or the ingestion of a large amount of sugar or caffeinated beverages. She denied the use/abuse of diuretics or laxatives, symptoms of bulimia, glue sniffing, substance abuse, or the ingestion of licorice or over-the-counter drugs. She did not seem to be overly concerned about her body weight. There was no family history of hypokalemia, hypertension, or paralytic episodes. On each of these occasions, other than the paralysis, the only findings of note were tachycardia (130 beats per minute) and mild systolic hypertension with a wide pulse pressure (150/70 mm Hg). There were no signs of hyperthyroidism. Because of the very low P _K (∼2.1 mmol/L), an intravenous infusion of KCl was started, and, as on the other occasions, she recovered promptly with the administration of a relatively small amount of K ⁺ ions. The laboratory data are provided below. In addition, all tests of thyroid function were in the normal range and investigations for a pheochromocytoma were negative. During the last admission, the insulin concentration in plasma was measured and it was in the normal range. The level of C-peptide in her blood was not elevated.

P _Na	mmol/L	141	P _Glucose	mg/dL (mmol/L)	133 (7.4)
P _K	mmol/L	2.1	P _Creatinine	mg/dL (μmol/L)	0.9 (77)
P _HCO3	mmol/L	22	BUN (P _urea )	mg/dL (mmol/L)	10 (3.4)
Arterial pH		7.38	Arterial PCO ₂	mm Hg	38
U _K	mmol/L	8	U _Creatinine	(g/L) (mmol/L)	0.8 (7)

Questions

What is the most likely basis for the repeated episodes of acute hypokalemia?
Was an adrenergic effect associated with the acute hypokalemia?
Are there any clues in her laboratory results to suggest what the cause of acute hypokalemia might be?

Part A

Principles of Physiology

Close to 98% of the total body K ⁺ ions is inside cells. The concentration of K ⁺ ions in cells is very high relative to its concentration in the ECF compartment. This is because K ⁺ ions in cells balance the charge on intracellular anions; these intracellular anions cannot exit from cells because they are macromolecules, and moreover, they are essential for cell functions (DNA, RNA, phospholipids, compounds for energy provision such as ATP and phosphocreatine). Hence, the vast majority of K ⁺ ions are is retained in cells, and only 2% of the total body K ⁺ ions are in the ECF compartment. Changes in the concentration of K ⁺ ions in the ECF compartment are, however, extremely important because they are proportionately much larger than changes in the concentration of K ⁺ ions in cells and it is the ratio of concentrations of K ⁺ ions across cell membranes that determines the RMP.

Acute K ⁺ ion homeostasis is achieved by control of the distribution of K ⁺ ions between the intracellular fluid (ICF) and ECF compartments (i.e., acute internal K ⁺ ion balance). Long-term K ⁺ homeostasis is achieved by control of the renal excretion of K ⁺ ions (external K ⁺ ion balance). Therefore, there must be sensitive regulatory mechanisms to minimize transient changes in the P _K before renal excretion of K ⁺ ions occurs.

General Concepts for the Movement of K ⁺ Ions across Cell Membranes

There are two conditions that are required for the movement of K ⁺ ions across cell membranes to occur. First, a sufficient electrochemical driving force across that membrane; and, second, a sufficient number of open K ⁺ ion channels in that membrane.

Driving Force for the Shift of K ⁺ Ions across Cell Membranes

The driving force for a shift of K ⁺ ions across cell membranes is a more negative voltage in the compartment in which K ⁺ ions will be located. There are two ways to generate a negative voltage across a cell membrane: (1) the import of anions or (2) the export of cations. A more negative voltage inside cells is generated by electrogenic exit of Na ⁺ ions via the sodium-potassium-ATPase (Na-K-ATPase) ( Figure 13-1 ). Because the Na-K-ATPase extrudes 3 Na ⁺ ions out of cells and imports only 2 K ⁺ ions into cells, and because export of intracellular macromolecular phosphate anions out of cells does not occur, the net result is the generation of a more negative voltage inside cells. This increase in intracellular negative voltage limits the exit of K ⁺ ions from cells down their chemical concentration difference.

Figure 13-1, Concept for the Movement of K + Ions Across Cell Membranes.

In the kidney, a transepithelial, lumen-negative electrical voltage drives the net secretion of K ⁺ ions by principal cells in the CDN (see Figure 13-1 ). This is generated when Na ⁺ ions are reabsorbed in an electrogenic fashion (i.e., reabsorption of Na ⁺ ions without their accompanying anions, which are usually Cl ⁻ ions). Reabsorption of Na ⁺ ions occurs via the epithelial Na ⁺ ion channel (ENaC) and is driven by the low concentration of Na ⁺ ions and the negative voltage inside principal cells, both of which are created by the activity of the Na-K-ATPase in their basolateral membranes.

Basis for the Selectivity of the K ⁺ Ion Channel for K ⁺ Ions

Na ⁺ ions are much smaller than K ⁺ ions, yet the K ⁺ ion channels are specific for K ⁺ ions.
Ions in solution have layers of water surrounding them; therefore, one must think in terms of their hydrated size.
Because of the chemical structure at the mouth of the K ⁺ ion channels, water shells surrounding K ⁺ ions are stripped off; therefore, K ⁺ ions become smaller than Na ⁺ ions and can pass through the channel, whereas Na ⁺ ions cannot.

Pathways for the Movement of K ⁺ Ions across Cell Membranes

K ⁺ ion channels are composed of a diverse family of membrane-spanning proteins that selectively conduct K ⁺ ions across cell membranes. K ⁺ ion channels have a pore that permits K ⁺ ions to cross the cell membrane and a selectivity filter that specifies K ⁺ ion as the ion species to move through the channel (see margin note). There are several different types of K ⁺ ion channels that permit K ⁺ ions to cross cell membranes. Some of these channels are regulated by voltage, others are regulated by ligands such as ionized calcium ions, and others are regulated by metabolites such as adenosine diphosphate (ADP) (these channels are called K _ATP channels). In the presence of a driving force, movement of K ⁺ ions through the specific K ⁺ ion channels depends on the number of K ⁺ ion channels, whether they are in an open or a closed configuration (their gating), and how quickly K ⁺ ions can move through them (their conductance).

When K ⁺ ions move out of cells, there is an increase in the net negative voltage inside cells. Because the concentration of K ⁺ ions in cells is higher than that predicted from its electrochemical equilibrium, control of the open probability of K ⁺ ion channels in cell membranes or their number is critical to regulate the magnitude of cell voltage, which in turn influences many essential cell functions. As illustrated in Figure 13-2 , regulation of K _ATP channels influences the gating of calcium ion channels as a result of a change in the voltage in cells (more negative if K _ATP channels are open—the converse is also true). Clinical examples where control of K _ATP channels has important effects on physiologic functions are discussed in the answers to [CR] .

Figure 13-2, Regulatory Roles for K ATP Channels in Cell Function.

From a renal perspective, secretion of K ⁺ ions in principal cells of the CDN requires that open K ⁺ ion channels, primarily the renal outer medullary K ⁺ ion channel (ROMK), must be present in the luminal membrane of these cells.

Question

13-1
Is the K _ATP channel regulated by ATP?

Part B

Shift of Potassium Ions across Cell Membranes

Increasing the Negative Voltage in Cells

To shift K ⁺ ions into cells and retain them inside cells, a more negative cell voltage is required. This is generated by increasing flux through Na-K-ATPase. There are three ways to acutely increase ion pumping by Na-K-ATPase: first, a rise in the concentration of its rate-limiting substrate—intracellular Na ⁺ ions; second, an increase in the affinity for Na ⁺ ions or in the maximum capacity for ion transport (V _max ) of the existing Na-K-ATPase units in cell membranes; and, third, an increase in the number of active Na-K-ATPase pumps in the cell membrane by recruitment of new units from an intracellular pool. A chronic increase in Na-K-ATPase pump activity requires the synthesis of new pump units, as occurs with exercise training or chronic excess thyroid hormone.

Raise the Intracellular Concentration of Na ⁺ Ions

The first mechanism to increase the flux of Na ⁺ through Na-K-ATPase is to raise the intracellular concentration of its rate-limiting substrate, intracellular Na ⁺ ions, because the extracellular concentration of K ⁺ ions is always high enough for maximal activity of the Na-K-ATPase. The impact of this increase in Na ⁺ ion pumping out of cells on the net cell voltage, however, depends on whether the Na ⁺ ion entry step into cells is electrogenic or electroneutral.

Abbreviations

P _Glucose , concentration of glucose in plasma
P _L-lactate , concentration of L-lactate in plasma
NHE-1, sodium hydrogen exchager-1
SLGT, sodium linked glucose transporter
EABV, effective arterial blood volume
DKA,diabetic ketoacidosis
MCT, monocarboxylic acid transporter

Electrogenic entry of Na ⁺ ions into cells

The Na ⁺ ion channel in cell membranes is normally closed by the usual magnitude of the negative intracellular voltage. If the Na ⁺ ion channel in skeletal muscle cell membranes were to open (e.g., by the release of acetylcholine in response to neuronal stimulation), the cell interior voltage becomes less negative. This is because one positive charge enters the cell per Na ⁺ ion transported into the cell, but only one-third of a positive charge exits the cell per Na ⁺ ion pumped out of the cell via Na-K-ATPase ( Figure 13-3 ). This decrease in intracellular negative voltage promotes the entry of ionized calcium (Ca ²⁺ ) via the voltage gated calcium ion channel, leading to muscle contraction. It also causes exit of K ⁺ ions from cells through open K ⁺ ion channels in the cell membrane and thus a rise in the concentration of K ⁺ ions in the ECF compartment.

Figure 13-3, Effect of Electroneutral Versus Electrogenic Entry of Na + Ions on the Negative Voltage in Cells.

Clinical implications

An abnormally large increase in the entry of Na ⁺ ions via Na ⁺ ion channels in cell membranes of skeletal muscle and its subsequent exit via Na-K-ATPase diminishes the magnitude of the intracellular negative voltage. This is the underlying pathophysiology of hyperkalemia in some patients with hyperkalemic periodic paralysis.

Major Settings in Which a Rapid Shift of K ⁺ into Cells Is Needed

After the ingestion of a large K ⁺ load : The major hormone involved is insulin; the major site for the shift of K ⁺ ions is into the liver.
After vigorous sprint : The major hormones involved are β ₂ -adrenergics, which are released in the “fight-or-flight” response.

Electroneutral entry of Na ⁺ into cells

This occurs when Na ⁺ ions enter cells in exchange for H ⁺ ions via the sodium-hydrogen cation exchanger-1 (NHE-1) (see Figure 13-3 ). The subsequent electrogenic exit of these Na ⁺ ions out of cells via the Na-K-ATPase results in a more negative voltage inside cells. NHE-1 in cell membranes is normally inactive. This can be deduced from the fact that it is an electroneutral exchanger and that the concentrations of its substrates (Na ⁺ ions in the ECF compartment and H ⁺ ions in the ICF compartment) are considerably higher than the concentrations of ions that reflect its transport activity (Na ⁺ ions in the ICF compartment and H ⁺ ions in the ECF compartment) in the steady state. There are two major activators of NHE-1: a spike in insulin level in the interstitial fluid compartment and a higher concentration of H ⁺ ions in the ICF compartment.

One major physiologic setting in which there is a need to shift K ⁺ ions into cells and to do so quickly is when there is a large dietary intake of K ⁺ ions (see margin note). Fruit and berries were the major sources of calories in the Paleolithic diet. Accordingly, this diet provided a large quantity of sugar (fructose and glucose) and K ⁺ ions. To prevent this K ⁺ ion load from entering the systemic circulation where it can be dangerous if it reaches the heart, the first line of defence is to induce a shift of this dietary load of K ⁺ ions into liver cells.

It is well known that there is a rise in the plasma L- lactate anions (P _L-lactate ) level in portal venous blood after absorption of dietary glucose. We suggested that a possible function of this high portal P _L-lactate is to prevent hyperkalemia in hepatic venous blood following the absorption of K ⁺ ions from the diet. The process begins by increasing the rate of glycolysis in enterocytes as a result of performing more metabolic work. This extra metabolic work occurs because the sodium linked glucose transporter (SLGT) in this location is SLGT-1. Hence, when 1 mmol of glucose is absorbed, 2 mmol of Na ⁺ ions must be absorbed. Therefore, more adenosine triphosphate (ATP) must be regenerated to absorb a given quantity of glucose than if the stoichiometry of the transporter was the absorption of 1 mmol of Na ⁺ ions per 1 mmol of glucose. Should glycolysis occur at a faster rate than pyruvate oxidation, L-lactic acid will be released into the portal vein. In the liver, the uptake of L-lactic acid on the monocarboxylic acid cotransporter and its subsequent dissociation inside the hepatocytes into H ⁺ ions and L-lactic acid anions could raise the concentration of H ⁺ ions in the submembrane region of the hepatocytes adjacent to NHE-1 and hence activate NHE-1 by binding to its modifier site. The electroneutral entry of Na ⁺ ions into hepatocytes and their subsequent exit via the Na-K-ATPase in an electrogenic fashion will lead to a higher negative intracellular voltage and hence the retention of K ⁺ ions in hepatocytes ( Figure 13-4 ). This mechanism requires the presence of insulin, which is released in response to the dietary sugar load with the ingestion of fruit and berries. This high concentration of insulin activates NHE-1 and also causes the translocation of more Na-K-ATPase units to the cell surface of hepatocytes.

Figure 13-4, Combined Actions of Insulin and l -Lactic Acid on a Shift of K + Ions into Hepatocytes.

Clinical implications

The infusion of L-lactic acid in fed rats and in rats with acute hyperkalemia induced by the infusion of HCl or KCl was associated with a fall in the concentration of K ⁺ ions in plasma (P _K ) from arterial blood samples. This was due to a shift of K ⁺ ions into the liver. A shift of K ⁺ ions into the liver was also observed with the infusion of Na lactate. The administration of a relatively large dose of insulin is the mainstay of therapy in patients with emergency hyperkalemia; hypoglycemia is a frequent complication. The administration of Na lactate with a smaller dose of insulin may provide an effective means to lower P _K with less risk of hypoglycemia in the emergency treatment of patients with hyperkalemia than when a higher dose of insulin alone is used. Further studies are required to examine the effectiveness of this approach.

Activate Pre-existing Na-K-ATPase

The second mechanism for increasing flux through Na-K-ATPase is also a rapid one. It involves activation of existing Na-K-ATPase units in the cell membrane. Unphosphorylated FXYD1 (phospholemann) binds to the α-subunit of the Na-K-ATPase, which diminishes the pump activity by decreasing its affinity for Na ⁺ ions and/or its V _max . Insulin causes phosphorylation of FXYD1 via atypical protein kinase C; this disrupts the interaction of FXYD1 with the α-subunit of Na-K-ATPase, which results in an increase in the affinity of the Na-K-ATPase for Na ⁺ ions and/or its V _max (see Figure 13-5 ).

Figure 13-5, Mechanism of the Effect of Insulin to Cause a Shift of K + Ions into Cells.

β ₂ -Adrenergic agonists activate adenylate cyclase, which leads to stimulation of the conversion of ATP to cyclic adenosine monophosphate (cAMP). This second messenger, in turn, activates protein kinase-A, which induces phosphorylation of the FXYD1, and results in an increase in the affinity of the Na-K-ATPase for intracellular Na ⁺ ( Figure 13-6 ). The increase in export of pre-existing intracellular Na ⁺ ions out of the cells leads to a higher negative voltage in cells and hence a shift of K ⁺ ions into cells.

Figure 13-6, Mechanism of the Effect of β 2 -Adrenergic Agonists to Cause a Shift of K + Ions into Cells.

This effect of β ₂ -adrenergic agonists to induce a shift of K ⁺ ions into cells is particularly important during vigorous exercise, the second major physiologic setting where there is a need to shift K ⁺ ions into cells quickly. In the fight-or-flight response, the stimulus for muscle contraction is the entry of Na ⁺ ions through the voltage-gated Na ⁺ ion channel during the depolarization phase of muscle action potential. This entry of positive charges diminishes the cell interior negative voltage, which promotes the entry of ionized Ca ²⁺ ions via the voltage-gated calcium channel, and therefore muscle contraction. It also causes K ⁺ ions to exit from exercising muscles during the repolarization phase of the muscle action potential. Hence, there is a danger of acute hyperkalemia (see margin note). To minimize this risk, the β ₂ -adrenergic effect of adrenaline released in this setting is exerted on hepatocytes and possibly on resting muscle cells, which obligates them to take up much of this K ⁺ ion load and thereby prevent a dangerous rise in the P _K .

In conditions associated with a large surge of catecholamines, the α-adrenergic effect dominates over the β-adrenergic effect. The α-adrenergic effect causes inhibition of the release of insulin, which may lead to a shift of K ⁺ ions out of cells. Therefore, hyperkalemia may develop.

Mechanisms for the Release of K ⁺ ions from Muscle Cells During Exercise

Na ⁺ ions enter muscle cells via open Na ⁺ ion channels during the depolarization phase of muscle action potential; this diminishes the negative voltage in cells. K ⁺ ions exit from muscle cells during repolarization.
Intracellular alkalinization occurs when phosphocreatine is hydrolyzed. This activates the extrusion of ${HC O_{3}}^{−}$ ${HC O_{3}}^{−}$ ions via the electroneutral $Cl / {HC O_{3}}^{−}$ $Cl / {HC O_{3}}^{−}$ anion exchanger with the entry of Cl ⁻ ions into cells. The subsequent electrogenic exit of Cl ⁻ ions from cells via Cl ⁻ ion channels diminishes the negative voltage in cells and hence K ⁺ ions exit cells (see Chapter 1 and Figure 13-5 ).

Clinical implications

An acute shift of K ⁺ ions into cells causing hypokalemia may be seen in conditions associated with a surge of catecholamines (e.g., patients with head trauma, subarachnoid hemorrhage, myocardial infarction, an extreme degree of anxiety). β ₂ -agonists may be used to shift K ⁺ ions into cells in patients with an emergency associated with hyperkalemia. On the other hand, nonspecific β-blockers are being used for therapy of the subtype of hypokalemic periodic paralysis associated with hyperthyroidism. In states with a very low effective arterial blood volume (EABV), the large α-adrenergic response leads to a shift of K ⁺ ions out of cells. This shift of K ⁺ ions out of cells is valuable to prevent a severe degree of hypokalemia when the underlying disorder is also associated with a large loss of K ⁺ ions (e.g., in patients with cholera or other infections causing severe secretory diarrhea). Hypokalemia becomes evident during therapy with restoration of the EABV.

Increase in the Number of Na-K-ATPase Units in Cell Membranes

Insulin

Another effect of insulin which induces a shift of K ⁺ ions into cells is by increasing the expression of Na-K-ATPase in cell membranes. This effect is mediated through phosphoinositide 3-kinase and extracellular signal regulated kinases 1 and 2 (ERK1/2). ERK1/2 kinases induce phosphorylation of the α subunit of the Na-K-ATPase, which promotes the translocation of Na-K-ATPase from an intracellular pool to the cell membrane (see Figure 13-5 ). Notwithstanding, the glucose transporter, GLUT4, and the Na-K-ATPase do not colocalize to the same intracellular vesicles in skeletal muscle and hence the effect of insulin to shift K ⁺ ions into cells is separate from its effect on glucose transport into these cells.

Clinical implications

Because of its multiple effects to induce a shift of K ⁺ ions into cells, insulin has been utilized to treat patients with an emergency caused by the adverse cardiac effects of hyperkalemia. In contrast, in patients with diabetic ketoacidosis (DKA), a lack of actions of insulin results in a shift of K ⁺ ions out of cells and the development of hyperkalemia despite a total body deficit of K ⁺ ions.

Exercise training

Having more Na-K-ATPase units in the cell membrane of skeletal muscle cells is not important at rest, but it is very important during vigorous exercise. There is a strong positive correlation between the activity of this ion pump, which is essential for recovery from cell depolarization, and the maximum ability for skeletal muscle to contract during vigorous exercise.

Thyroid hormones

Hyperthyroidism is also associated with a higher content of Na-K-ATPase units in the cell membrane.

Clinical implications

A severe degree of hypokalemia due to a shift of K ⁺ ions into cells is seen in patients with the thyrotoxic subtype of hypokalemic periodic paralysis. These patients can be managed effectively during their attacks with the administration of nonselective β-blockers and a small dose of KCl (see Chapter 14 for more details). Although not supported by epidemiological data, it is thought that many of these patients have attacks of acute hypokalemia and paralysis after eating a large amount of carbohydrates. Perhaps the effect of high levels of insulin to activate NHE-1, phosphorylate FXYD1, and cause the translocation of Na-K-ATPase into cell membranes, in addition to the effect of thyroid hormone to cause the synthesis of more Na-K-ATPase units, may lead to the severe degree of hypokalemia.

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Introduction

Objectives

Case 13-1: Why Did I Become So Weak?

Questions

Part A

Principles of Physiology

General Concepts for the Movement of K + Ions across Cell Membranes

Driving Force for the Shift of K + Ions across Cell Membranes

Pathways for the Movement of K + Ions across Cell Membranes

Question

Part B

Shift of Potassium Ions across Cell Membranes

Increasing the Negative Voltage in Cells

Raise the Intracellular Concentration of Na + Ions

Electrogenic entry of Na + ions into cells

Clinical implications

Electroneutral entry of Na + into cells

Clinical implications

Activate Pre-existing Na-K-ATPase

Clinical implications

Increase in the Number of Na-K-ATPase Units in Cell Membranes

Insulin

Clinical implications

Exercise training

Thyroid hormones

Clinical implications

You're Reading a Preview

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Raise the Intracellular Concentration of Na ⁺ Ions

Electrogenic entry of Na ⁺ ions into cells

Electroneutral entry of Na ⁺ into cells