Sodium

 The sodium ion (Na+) is an essential mineral for our body because it regulates the osmolality of the extracellular fluid and plays a key role in many physiological processes, from the generation of nerve impulses to renal function.

Sodium is an essential component for the excitability properties of both nerve and muscle tissue

 Synaptic transmission and the generation of the action potential are both dependent on the presence of N

Treatment of brain injury can contribute to, and complicate the diagnosis of, sodium disorders.

 Synaptic transmission and the generation of the action potential are both dependent on the presence of N

 Na+ is lost continuously through urine, feces, and sweat. Thus, to maintain proper bodily balance, we need to replace losses by the ingestion of food containing this cation. 

In these mammals, the epithelial sodium channel (ENaC) works as low-salt receptor,  a diuretic drug, which selectively blocks the channel at submicromolar concentrations 

The epithelial sodium channel (ENaC) is a key membrane protein underlying absorption of Na+ in many epithelia, such as those found in kidney, colon, and lung

The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [2,4,6-7,13]. In these epithelia, Na⁺ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC. The Na⁺ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na⁺/K⁺ ATPase located on the basolateral membrane [11]. As Na⁺ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na⁺ flow is accompanied by a flow of water accompanying Na⁺ ions [1]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [12]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [9,12].

In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [5]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [5]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on non-cilial cell-surface [5]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [13]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [13]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation, and cell migration [5,7].

Some authors found that indeed the presence of amiloride reduced the perceived saltiness of the NaCl solutions, 

application of NaCl solution to the tongue mucosa produces a transepithelial current due to the movement of ions across the epithelium [9,34,35]. This current is believed to be sustained mainly by Na+ entering taste cells via the apical ENaC since amiloride strongly reduces it.

amiloride (100 μM) was able to reduce the voltage drop caused by NaCl application

Amiloride is a potassium-sparing diuretic (water pill) that prevents your body from absorbing too much salt and keeps your potassium levels from getting too low. Amiloride is used to treat or prevent hypokalemia (low potassium levels in the blood) in people with high blood pressure or congestive heart failure.

The study of ENaC is tightly linked to the use of amiloride as pharmacological tool [43] . Amiloride affects several membrane transporters and ion channels; in the submicromolar concentration range, however, it is a specific reversible blocker of ENaC

Primary active transport 

1. Characteristics of primary active transport 

 

 ■ is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition. 2. Examples of primary active transport a. Na+,K+-ATPase (or Na+–K+ pump) in cell membranes transports Na+ from intracellular to extracellular fluid and K+ from extracellular to intracellular fluid; it maintains low intracellular [Na+] and high intracellular [K+].

■ Both Na+ and K+ are transported against their electrochemical gradients. 

■ The usual stoichiometry is 3 Na+/2 K+

. ■ Specific inhibitors of Na+,K+-ATPase are the cardiac glycoside drugs ouabain and digitalis. b. Ca2+-ATPase (or Ca2+ pump) in the sarcoplasmic reticulum (SR) or cell membranes transports Ca2+ against an electrochemical gradient.

 ■ Sarcoplasmic and endoplasmic reticulum Ca2+-ATPase is called SERCA. c. H+,K+-ATPase (or proton pump) in gastric parietal cells transports H+ into the lumen of the stomach against its electrochemical gradient.

 ■ It is inhibited by proton pump inhibitors, such as omeprazole. E. Secondary active transport 1. Characteristics of secondary active transport a. The transport of two or more solutes is coupled. b. One of the solutes (usually Na+) is transported “downhill” and provides energy for the “uphill” transport of the other solute(s). c. Metabolic energy is not provided directly, but indirectly from the Na+ gradient that is maintained across cell membranes. Thus, inhibition of Na+,K+-ATPase will decrease transport of Na+ out of the cell, decrease the transmembrane Na+ gradient, and eventually inhibit secondary active transport. d. If the solutes move in the same direction across the cell membrane, it is called cotransport, or symport. 

■ Examples are Na+–glucose cotransport in the small intestine and Na+–K+–2Cl– cotransport in the renal thick ascending limb. e. If the solutes move in opposite directions across the cell membranes, it is called counter - transport, exchange, or antiport. 

■ Examples are Na+–Ca2+ exchange and Na+–H+ exchange.

2. Example of Na+–glucose cotransport (Figure 1-1) a. The carrier for Na+–glucose cotransport is located in the luminal membrane of intestinal mucosal and renal proximal tubule cells. b. Glucose is transported “uphill”; Na+ is transported “downhill.” c. Energy is derived from the “downhill” movement of Na+. The inwardly directed Na+ gradient is maintained by the Na+–K+ pump on the basolateral (blood side) membrane. Poisoning the Na+–K+ pump decreases the transmembrane Na+ gradient and consequently inhibits Na+–glucose cotransport.

3. Example of Na+–Ca2+ countertransport or exchange (Figure 1-2) a. Many cell membranes contain a Na+–Ca2+ exchanger that transports Ca2+ “uphill” from low intracellular [Ca2+] to high extracellular [Ca2+]. Ca2+ and Na+ move in opposite directions across the cell membrane. b. The energy is derived from the “downhill” movement of Na+. As with cotransport, the inwardly directed Na+ gradient is maintained by the Na+–K+ pump. Poisoning the Na+–K+ pump therefore inhibits Na+–Ca2+ exchange.

Inorganic materials are as much an integral component of protoplasm as proteins, carbohydrates, and lipids; without them physiologic processes are impossible. Among the inorganic

constituents of protoplasm are calcium, potassium, sodium, and magnesium present as carbonates, chlorides, phosphates, and sulfates; small quantities of iron, copper, and iodine; and trace elements such as cobalt, manganese, zinc, and other metals. The inorganic materials have many functions, including maintenance of intracellular and extracellular osmotic pressures, transmission of nerve impulses, contraction of muscle, adhesiveness of cells, activation of enzymes, transport of oxygen, and maintenance of the rigidity of tissues such as bone.   

The plasmalemma of these regions is rich in ion channel proteins, in particular sodiumpotassium-ATPase.

The plasmalemma of the ruffled border is rich in sodium/potassium ATPase and carbonic anhydrase that produces hydrogen ions

The extracellular fluid contains large

amounts of sodium, chloride, and bicarbonate ions plus

nutrients for the cells, such as oxygen, glucose, fatty acids,

and amino acids. It also contains carbon dioxide

The intracellular fluid differs significantly from the

extracellular fluid; for example, it contains large amounts

of potassium, magnesium, and phosphate ions instead of

the sodium and chloride ions found in the extracellular

fluid.

Hormones are transported in the extracellular

fluid to all parts of the body to help regulate cellular

function. For instance, thyroid hormone increases

the rates of most chemical reactions in all cells, thus helping

to set the tempo of bodily activity. Insulin controls

glucose metabolism; adrenocortical hormones control

sodium ion, potassium ion, and protein metabolism; and

parathyroid hormone controls bone calcium and phosphate.

The liver and pancreas regulate

the concentration of glucose in the extracellular fluid,

and the kidneys regulate concentrations of hydrogen,

sodium, potassium, phosphate, and other ions in the

extracellular fluid.

In addition to membrane transport of sodium, energy

from ATP is required for membrane transport of potassium

ions, calcium ions, magnesium ions, phosphate ions chloride ions, urate ions, hydrogen ions, and many other

ions and various organic substances.

Potassium channels permit passage of potassium ions

across the cell membrane about 1000 times more readily

than they permit passage of sodium ions. This high degree

of selectivity, however, cannot be explained entirely by

molecular diameters of the ions since potassium ions

are slightly larger than sodium ions.

Electrical current flowing

through a single sodium channel when there was an

approximate 25-millivolt potential gradient across the

membrane.

Osmosis occurs

from the pure water into the sodium chloride solution.

pressure were applied to the sodium chloride

solution, osmosis of water into this solution would

be slowed, stopped, or even reversed. The exact amount

of pressure required to stop osmosis is called the osmotic

pressure of the sodium chloride solution.

Some energy source must cause excess movement

of potassium ions to the inside of cells and excess

movement of sodium ions to the outside of cells. When a

cell membrane moves molecules or ions “uphill” against a

concentration gradient (or “uphill” against an electrical or

pressure gradient), the process is called active transport.

Different substances that are actively transported

through at least some cell membranes include sodium

ions, potassium ions, calcium ions, iron ions, hydrogen

ions, chloride ions, iodide ions, urate ions, several

different sugars, and most of the amino acids.

Among the substances that are transported by primary

active transport are sodium, potassium, calcium,

hydrogen,

chloride, and a few other ions.

The active transport mechanism that has been studied

in greatest detail is the sodium-potassium (Na+-K+)

pump, a transport process that pumps sodium ions outward

through the cell membrane of all cells and at the

same time pumps potassium ions from the outside to

the inside. This pump is responsible for maintaining the

sodium and potassium concentration differences across

the cell membrane, as well as for establishing a negative

electrical voltage inside the cells. Indeed, Chapter 5 shows

that this pump is also the basis of nerve function, transmitting

nerve signals throughout the nervous system.

When two potassium ions bind on the outside of

the carrier protein and three sodium ions bind on the

inside, the ATPase function of the protein becomes activated.

As with other enzymes, the Na+-K+ ATPase pump can

run in reverse. If the electrochemical gradients for Na+ and

K+ are experimentally increased enough so that the energy

stored in their gradients is greater than the chemical energy

of ATP hydrolysis, these ions will move down their concentration

gradients and the Na+-K+ pump will synthesize ATP

from ADP and phosphate. The phosphorylated form of the

Na+-K+ pump, therefore, can either donate its phosphate to

ADP to produce ATP or use the energy to change its conformation

and pump Na+ out of the cell and K+ into the cell.

The relative concentrations of ATP, ADP, and phosphate, as

well as the electrochemical gradients for Na+ and K+, determine

the direction of the enzyme reaction. For some cells,

such as electrically active nerve cells, 60 to 70 percent of the

cells’ energy requirement may be devoted to pumping Na+

out of the cell and K+ into the cell.

The Na+-K+ Pump is Important For Controlling Cell

Volume. One of the most important functions of the

Na+-K+ pump is to control the volume of each cell.

Without function of this pump, most cells of the body

would swell until they burst. The mechanism for controlling

the volume is as follows: Inside the cell are large numbers

of proteins and other organic molecules that cannot

escape from the cell. Most of these are negatively charged

and therefore attract large numbers of potassium, sodium,

and other positive ions as well. All these molecules and

ions then cause osmosis of water to the interior of the

cell. Unless this is checked, the cell will swell indefinitely

until it bursts. The normal mechanism for preventing this

is the Na+-K+ pump. Note again that this device pumps

three Na+ ions to the outside of the cell for every two K+

ions pumped to the interior. Also, the membrane is far

less permeable to sodium ions than to potassium ions,

so once the sodium ions are on the outside, they have a

strong tendency to stay there. Thus, this represents a net

loss of ions out of the cell, which initiates osmosis of water

out of the cell as well.

If a cell begins to swell for any reason, this automatically

activates the Na+-K+ pump, moving still more ions

to the exterior and carrying water with them. Therefore,

the Na+-K+ pump performs a continual surveillance role

in maintaining normal cell volume.

Electrogenic Nature of the Na+-K+ Pump. The fact that

the Na+-K+ pump moves three Na+ ions to the exterior for

every two K+ ions to the interior means that a net of one

positive charge is moved from the interior of the cell to the

exterior for each cycle of the pump. This creates positivity outside the cell but leaves a deficit of positive ions inside the

cell; that is, it causes negativity on the inside. Therefore, the

Na+-K+ pump is said to be electrogenic because it creates an

electrical potential across the cell membrane. As discussed

in Chapter 5, this electrical potential is a basic requirement

in nerve and muscle fibers for transmitting nerve and muscle

signals.

When sodium ions are transported out of cells by primary

active transport, a large concentration gradient of

sodium ions across the cell membrane usually develops—

high concentration outside the cell and low concentration

inside. This gradient represents a storehouse of energy

because the excess sodium outside the cell membrane is

always attempting to diffuse to the interior. Under appropriate

conditions, this diffusion energy of sodium can pull

other substances along with the sodium through the cell

membrane. This phenomenon is called co-transport; it is

one form of secondary active transport

Co-Transport of Glucose and Amino Acids

Along with Sodium Ions

Glucose and many amino acids are transported into most

cells against large concentration gradients; the mechanism

of this is entirely by co-transport, as shown in Figure

4-13. Note that the transport carrier protein has two

binding sites on its exterior side, one for sodium and one for glucose. Also, the concentration of sodium ions is high

on the outside and low inside, which provides energy for

the transport. A special property of the transport protein

is that a conformational change to allow sodium movement

to the interior will not occur until a glucose molecule

also attaches. When they both become attached,

the conformational change takes place automatically, and

the sodium and glucose are transported to the inside of

the cell at the same time. Hence, this is a sodium-glucose

co-transport mechanism. Sodium-glucose co-transporters

are especially important mechanisms in transporting

glucose across renal and intestinal epithelial cells, as discussed

in Chapters 27 and 65.

molecular characteristics.

Sodium co-transport of glucose and amino acids

occurs especially through the epithelial cells of the intestinal

tract and the renal tubules of the kidneys to promote

absorption of these substances into the blood, as is discussed

in later chapters.

Two especially important counter-transport mechanisms

(transport in a direction opposite to the primary ion) are

sodium-calcium counter-transport and sodium-hydrogen

counter-transport.

Sodium-calcium counter-transport occurs through all

or almost all cell membranes, with sodium ions moving

to

the interior and calcium ions to the exterior, both bound

to the same transport protein in a counter-transport

mode. This is in addition to primary active transport of

calcium that occurs in some cells.

Sodium-hydrogen counter-transport occurs in several

tissues. An especially important example is in the proximal

tubules of the kidneys, where sodium ions move

from the lumen of the tubule to the interior of the tubular

cell, while hydrogen ions are counter-transported into

the tubule lumen. As a mechanism for concentrating

hydrogen ions, counter-transport is not nearly as powerful

as the primary active transport of hydrogen ions that

occurs in the more distal renal tubules, but it can transport

extremely large numbers of hydrogen ions, thus making

it a key to hydrogen ion control in the body fluids, as

discussed in detail in Chapter 30.

First, sodium, potassium, and chloride ions are

the most important ions involved in the development of

membrane potentials in nerve and muscle fibers, as well as

in the neuronal cells in the nervous system.

First, let us recall from Chapter 4 that

all cell membranes of the body have a powerful Na+-K+

pump that continually transports sodium ions to the outside

of the cell and potassium ions to the inside, as illustrated

on the left-hand side in Figure 5-4. Further, note

that this is an electrogenic pump because more positive

charges are pumped to the outside than to the inside

(three Na+ ions to the outside for each two K+ ions to the

inside), leaving a net deficit of positive ions on the inside;

this causes a negative potential inside the cell membrane.

The Na+-K+ pump also causes large concentration gradients

for sodium and potassium across the resting nerve

membrane.

addition of

slight permeability of the nerve membrane to sodium ions,

caused by the minute diffusion of sodium ions through

the K+-Na+ leak channels. The ratio of sodium ions from

inside to outside the membrane is 0.1, and this gives a calculated

Nernst potential for the inside of the membrane of

+61 millivolts.

Contribution of the Na+-K+ Pump. In Figure 5-5C,

the Na+-K+ pump is shown to provide an additional contribution

to the resting potential. In this figure, there is continuous

pumping of three sodium ions to the outside for

each two potassium ions pumped to the inside of the membrane.

The fact that more sodium ions are being pumped

to the outside than potassium to the inside causes continual

loss of positive charges from inside the membrane;

this creates an additional degree of negativity (about −4

millivolts additional) on the inside beyond that which can

be accounted for by diffusion alone. Therefore, as shown

in Figure 5-5C, the net membrane potential with all these

factors operative at the same time is about −90 millivolts.

When sodium is the only

permeant ion in the solutions inside and outside the squid

axon, the voltage clamp measures current flow only through

the sodium channels. When potassium is the only permeant

ion, current flow only through the potassium channels is

measured.

for the original establishment

of the resting potential. That is, sodium ions

that have diffused to the interior of the cell during the

action potentials and potassium ions that have diffused

to the exterior must be returned to their original state by

the Na+-K+ pump. Because this pump requires energy for

operation, this “recharging” of the nerve fiber is an active

metabolic process, using energy derived from the adenosine

triphosphate (ATP) energy system of the cell 

Mechanisms of Smooth Muscle:

Some

hormone receptors in the smooth muscle membrane open

sodium or calcium ion channels and depolarize the membrane,

the same as after nerve stimulation.

Inhibition, in contrast, occurs when the hormone (or

other tissue factor) closes the sodium and calcium channels

to prevent entry of these positive ions; inhibition

also occurs if the normally closed potassium channels are

opened, allowing positive potassium ions to diffuse out of

the cell. Both of these actions increase the degree of negativity

inside the muscle cell, a state called hyperpolarization,

which strongly inhibits muscle contraction

In cardiac muscle, the action potential is caused by

opening of two types of channels: (1) the same fast sodium

channels as those in skeletal muscle and (2) another entirely

different population of slow calcium channels, which are

also called calcium-sodium channels. This second population

of channels differs from the fast sodium channels in

that they are slower to open and, even more important,

remain open for several tenths of a second. During this

time, a large quantity of both calcium and sodium ions

flows through these channels to the interior of the cardiac

muscle fiber, and this maintains a prolonged period

of depolarization, causing the plateau in the action potential.

Calcium ions are

also removed from the cell by a sodium-calcium exchanger.

The sodium that enters the cell during this exchange is

then transported out of the cell by the sodium-potassium

ATPase pump. As a result, the contraction ceases until

a new action potential comes along.

Therefore, between heartbeats,

influx of positively charged sodium ions causes a slow

rise in the resting membrane potential in the positive

direction.

Two general classes of drugs are used to treat hypertension:

(1) vasodilator drugs that increase renal blood

flow and (2) natriuretic or diuretic drugs that decrease

tubular reabsorption of salt and water.

Vasodilator drugs usually cause vasodilation in many

other tissues of the body, as well as in the kidneys. Different

ones act in one of the following ways: (1) by inhibiting

sympathetic nervous signals to the kidneys or by blocking

the action of the sympathetic transmitter substance

on the renal vasculature and renal tubules, (2) by directly

relaxing the smooth muscle of the renal vasculature, or

(3) by blocking the action of the renin-angiotensin system

on the renal vasculature or renal tubules.

Those drugs that reduce reabsorption of salt and

water by the renal tubules include especially drugs that

block active transport of sodium through the tubular

wall; this blockage in turn also prevents the reabsorption

of water, as explained earlier in the chapter. These natriuretic

or diuretic drugs are discussed in greater detail in

Chapter 31.

Active transport of sodium and potassium through

the cell membrane is greatly diminished. As a result,

sodium and chloride accumulate in the cells and potassium

is lost from the cells. In addition, the cells begin

to swell.