BOBY FLUID PHYSIOLOGY

Objectives after studying this chapter, you should be able to . . .

1. Know the composition of extracellular and intracellular body fluids.

2. Explain osmosis, osmolarity and osmotic pressure, and tonicity of the body fluids.
3. Know the forces producing movement of substances between compartments.
4. Describe the process of endocytosis and exocytosis.
5. Describe the primary factors (Starling forces) that determine fluid movement
through the capillary membrane and the formation of interstitial fluid and lymph.
6. Describe the intake versus output of water.
Water is by far the most abundant components of the body, constituting about 60% in
young males and about 50% in young women of the total body weight (TBW) (lower
level in fat, upper level in thin, 80% in infants). The percentage of body water varies
inversely with the body’s fat content and age. The total body water in males is larger
than in females because the latter have a somewhat larger amount of subcutaneous
fat. In both sexes, the percentage of body water
decreases with age, which can be attributed primarily
to an increase of adipose tissue. The body water is
distributed into two major fluid compartments,
extracellular fluid (ECF) (figure 2.1), which contains
approximately 20% of TBW, and intracellular fluid
(ICF), which contains approximately 40% of the TBW.

Extra cellular fluid (20% of the TBW):

1. The interstitial fluid (the fluids between cells and in
lymphatic) which constitutes about 15% of the
TBW.
2. Plasma constitutes about 4% of the TBW.
3. Transcellular fluids (include fluid in
the gastrointestinal, biliary, and urinary tracts,
the intraocular and cerebrospinal fluids, and fluid in
the serosal spaces, such as the pleural, peritoneal,
and pericardial fluid) constitutes about 1% of the TBW. Figure 2.1: Water distribution between
body compartments.
 Plasma and interstitial fluid: Have very similar composition, with Na+ as the
predominant cation and CI- and HCO3– as the predominant anions (figure 2.2).
However, an important difference between plasma and interstitial fluid is the larger
concentration of proteins in the plasma. This difference
exists because the capillary endothelium is freely permeable
to water and to small solutes (the so-called crystalloids), such
as inorganic icons, glucose, and urea, but has limited
permeability to larger solutes (colloidal particles), such as
large proteins and lipids. Thus, interstitial fluid is an ultra
filtrate of plasma.
In spite of the differences in ion concentrations and
the total concentration of the similar charges, electrical
neutrality is maintained within each compartment, i.e., the
total number of cationic charges equals the total number of
anionic charges.

Figure 2.2: Relative concentration of

various anions and cations between
ECF and ICF.
Intracellular fluid (40% of the TBW): In contrast to ECF, the intracellular fluid (ICF)
contains relatively low concentration of Na+, CI-, and HCO3-. Instead, the predominant
cation in ICF is K+ and Mg++, while the predominant anions are organic phosphates
(e.g. ATP, ADP, and AMP) and proteins. These striking composition differences
between ICF and ECF can be attributed mainly to presence of the Na +-K+ ATPase pump
in cell membranes which actively transports three sodium ions from and two potassium
ions into cells, thereby accounting for the high sodium ion and low potassium ion
concentrations in ECF and the opposite picture inside ICF.

Osmosis, osmotic pressure and osmolarity of the body fluids:

The Osmosis is the diffusion or flow of water (solvent) molecules across a
semipermeable membrane (through channel proteins called aquaporins) into a region
in which there is a high concentration of a solute to which the membrane is
impermeable (figure 2.3). In another word; is the diffusion or flow of water molecules
from region of high concentration of water molecules across a semipermeable
membrane (through channel proteins called aquaporins) into a region of low
concentration of water molecules.
 Cells can regulate the rate of osmosis by adding aquaporins to the plasma
membrane or removing them. Certain cells of the kidneys, for example, install or take
away aquaporins to regulate the rate of water loss from the body in the urine

Figure 2.3: Osmosis through semipermeable

membrane.
The osmotic pressure is an attractive force of the solute particles to water
molecules that drives water molecules to move from solution 1 to solution 2 as a result
of the presence of solute in solution 2. Consequently, the osmotic pressure difference
across the membrane causes water to flow from solution
1 (which has no or less solute concentration and consequently lower osmotic pressure)
to solution 2 (which has a higher solute concentration and a higher osmotic pressure)
(figure 2.3). The number of the solute particles determines the magnitude of the
osmotic pressure of the solution in which it is dissolved. Oncotic pressure, or colloid
osmotic pressure, is a form of osmotic pressure exerted by large molecules such as
proteins (notably albumin), in a blood vessel's plasma or interstitial fluid that usually
tends to pull water toward these molecules.

 Each mole of a substance contains Avogadro's constant (6.022×1023) of molecules.

Molarity of a substance is the concentration of non-dissociated substance (in moles)
per one L (kg) of water.
 The osmolarity (osmole) is the concentration of osmotically active particles (the
molecules or the particles which attract water to it) in one liter of a solution (mol/L
H2O).
The osmolality (osmole) is the concentration of osmotically active particles (the
molecules or the particles which attract water to it) in one kg of a solution (mol/Kg
H2O).
 The number of osmotically active particles in any fluid is determined by: The number
of moles per liter (or kg) of water X the numbers of osmotically active particles
released into solution when the solute is dissolved.

Therefore;
One Avogadro's constant molecules of a substance/L H2O = 1 Mole of substance/L H2O
(MOLARITY) = 1 Mole X the numbers of osmotically active particles released into
solution when the solute is dissolved (OSMOLARITY, Osmole of substance /L H2O).

Examples:
ʘ 5% of glucose in water has a molarity of 300 mMoles/L H 2O, and because the glucose
molecules in water do not dissociated, it has an osmolarity of 300 mOsmol/L H 2O.
ʘ 0.9% NaCl in water has a molarity of 150 mMoles/L H2O, and because each NaCl
molecule in water is dissociated into two osmotically active particles (Na + and Cl- ions);
it has an osmolarity of 300 mOsmol/L
H2O.
Therefore, 5% of glucose in water and 0.9% NaCl in water have different
molarity but identical osmolarity and consequently identical osmotic pressure.

Therefore, osmolality of the plasma and ECF is mainly due to sodium ions,
chloride ions, bicarbonate ions, and to less extent due to other ions, urea, glucose, and
proteins. The osmolality of the ICF is mainly due to potassium ions, magnesium ions,
organic phosphates, proteins and other nitrogen containing solutes. In spite of the
differences in composition, these fluids have essentially identical total osmolality.

In spite of the differences in composition of the body fluids, they have

essentially identical total osmolalities of about of about 290-300 mOsmol/ kg H 2O.
This is because the capillary endothelium and cell membranes are freely permeable to
water, allowing the plasma, interstitial fluid, and ICF to be isomostic (iso-osmotic). It
should be noted that the iso-osmolality principals applies primarily to the main body
fluid compartments. Other body fluids can differ significantly from 290 mOsmol/kg H 2O,
including the peritubular interstitial fluid of the renal medulla (as much as 1200 mOsmol
/ Kg H2O) and certain transcellular fluids such as urine whose osmolality can vary from
70-1200 mOsmol/ Kg H2O.

The term tonicity is used to describe the effective osmotic pressure of a solution
relative to plasma in which the normal body cells can be placed without causing either
swelling or shrinking. A solution with effective osmotic pressure as plasma is said to be
isotonic which corresponds to 0.9 % solution of NaCl or a 5% glucose solution. Those
solutions with greater pressure are hypertonic in which the normal body cells shrink
when they are placed in it. Those solutions with lesser pressure are hypotonic in which
the normal body cells swell when they are placed in it. Osmolarity and tonicity are
related, but different concepts. The terms are different because osmolarity takes into
account the total concentration of penetrating solutes (solutes that can diffuse through
cell membrane easily such as urea) and non-penetrating solute (solutes that cannot
diffuse through cell membranes such as NaCl); whereas tonicity takes into account the
total concentration of only non-penetrating solutes. For example, if a solution had 150
mMol/L of NaCl and 100 mMol/L of Urea the tonicity of the solution would be 300
mOsmol/L for only the NaCl (non-penetrating solutes). The osmolarity of the solution,
however, would be both NaCl and Urea and would therefore be 400 mOsmol/L. If we
were to compare the osmolarity and tonicity of this solution to that of a typical cell (300
mOsmol/L), then it would be isotonic (both have tonicities of 300 mOsmol/L) but
hyperosmotic (the solution has an osmolarity of 400 mOsmol/L while the cell has an
osmolarity of 300 mOsmol/L).
If water is added to the extracellular fluid by injection into the blood stream, by
injection beneath the skin, or by ingesting water followed by absorption from
gastrointestinal tract into the blood, the water dilutes the extracelluar fluids, causing it
to become hypotonic with respect to the interstitial and to the intracellular fluids,
osmosis begins immediately at the capillary and cells membranes, with large amounts
of water passing to the interstitial and to the interiors of the cells, within a few minutes
the water becomes distributed almost evenly amongst all the extracellular and
intracellular fluid compartments, and all compartments will have the same osmolalities
(i.e. the same tonicity). Excess water intake and dilution of extracellular fluid called
overhydration or water intoxication.
If water is lost from the body by evaporation from the skin, lungs, or excretion
of a very dilutes urine as in diabetes insipidus, or loss in feces as in diarrhea, the water
will leave the extracellular fluid compartment causing this compartment to have a
hypertonic fluid in respect to the fluids in the intracellular compartments. Osmosis
begins immediately at the cell membrane with water passing to the interstitium and
plasma and distributed uniformly between the three compartments, so that all the
three compartments will have the same osmolalities. The overall effect is called
dehydration.

A principal laboratory test that indicates fluid deficit or excess is the urine specific
gravity, which measures urine osmolarity. Normal range = .10.1-.10.1. As fluid volume
in the blood increases, the water excreted in the urine increases, making it more dilute
and causing the specific gravity of the urine to decrease (below 1.015). Conversely, as
the fluid volume in the blood decreases, as occurs in dehydration, the water excreted
in the urine decreases, making it more concentrated and causing the specific gravity of
the urine to increase (above 1.025).
Hematocrit levels also can indirectly indicate fluid volume in the blood. Since the test
measures the number of blood cells per volume of blood, increased fluid in the blood,
that is, hypervolemia will dilute the blood cells and cause the hematocrit level to
decrease. Consequently, too little fluid in the blood, that is, hypovolemia, will cause
hemoconcentration and result in a high hematocrit level. It is therefore important to
consider the patient’s hydration level when interpreting laboratory values1
The test for serum osmolality measures the concentration of osmotically active
particles dissolved in blood. Sodium is a major contributor to osmolality in extracellular
fluid. Serum osmolality generally ranges from 290 to 300 mOsmol/kg of H 2O. When
fluid volume decreases, as in dehydration, serum osmolarity increases and vise versa.

Forces producing movement of substances between Compartments

[1] Simple diffusion: In which the molecules or ions tend to spread from regions to
another regions according to electro-chemical gradients through the cell membrane
lipid bilayer (for lipid soluble substances such as oxygen, nitrogen, CO 2, anesthetic
gases, and alcohol) or through cell membrane channel proteins (for water and
water soluble substances such as ions) until the concentration is uniform across the
membrane. It does not require metabolic energy and therefore, it is passive.
Diffusion from one region to another is affected by:
(a) The concentration gradient. Diffusion of substances through cell membrane
is directly proportional to the concentration gradient of that substance
across the membrane.
(b) The electrical gradient. Whenever there is a potential difference between
two regions, positively charged ions move along this electrical gradient to
the more
negative
charged region,
negatively
charged ions
move in the
opposite
direction. (c)
The thickness of
the boundary.
Diffusion of substances through cell membrane is
inversily proportional to the thickness of the membrane
(d) The cross sectional area of the boundary across which diffusion is tacking
place. Diffusion of substances through cell membrane is directly proportional to
the cross sectional area of the boundary across which diffusion is taking place.
(e) Temperature. Diffusion is driven by the kinetic energy of the particles,
and temperature is a measure of that kinetic energy. The warmer a substance is,
the more rapidly its particles diffuse. This is why sugar diffuses more quickly
through hot tea than through iced tea. (f) Membrane permeability. Diffusion
through a membrane depends on how permeable it is to the particles. Cells can
adjust their permeability to such a substance by adding channel proteins to the
 membrane or taking them away. Kidney tubules, for example, do this as a way
of controlling the amount of water eliminated from the body.
(g) The diffusion coefficient of the gas in the substance of the membrane.
[2] Filtration: Filtration is the process by which water and water soluble substances is
forced through an epithelial layer or other barrier due to a difference in hydrostatic
pressure on the two sides.
Filtration is affected by
(a) The pressure gradient across the membrane,
(b) The surface area of the membrane,
(c) The diameter of the membrane pores,
(d) The size of the filtered molecules1
In physiology, the most important case of filtration is seen in the blood
capillaries, where blood pressure forces fluid through gaps in the capillary wall. This is
how water and water soluble substances (salts, nutrients, and other solutes) are
transferred from the bloodstream to the tissue fluid and how the kidneys filter wastes
from the blood.
[3] Osmosis.
[4] Carrier-mediated transport: It is the transport of substances across the cell
membrane mediated by a carrier protein.
This type of transport is characterized by the following:
[i] Stereospecificity: For example, D-glucose is transported by
facilitated diffusion, but the L-isomer is not.
[ii] Saturation: The transport rate increases as the concentration of
the solute increases, until the carriers are saturated (the transport maximum, or
Tm) then no more increase in transport in spite of increase in concentration of
solute, for example, renal Tm of glucose..
[iii] Competition: Structurally related solutes compete for transport
sites on carrier molecules. For example, galactose is a competitive inhibitor of
glucose transport in the small intestine.
The direction of the carrier-mediated transport is:
(a) Uniport transport: If one transported substance is moving in one direction
and without an associated transport of another substance (as in the
facilitated diffusion of glucose).
(b) Co-transport or symport: If two or more of the transported substances are
moving in the same direction (as Na +-glucose co-transport, Na+-amino acids
co-transport, and Na+-K+-2Cl- cotransport).
(c) Counter-transport or antiport: If two or more of the transported substances
are moving in the opposite direction (as Na +-Ca2+ counter-transport and Na+-
H+ counter transport).
Carrier-mediated transports are of two main types:
[A] Facilitated diffusion: When the
carrier-mediated transport occurs
according to electrochemical gradient
and the energy is not required
(passive), the process is called
facilitated diffusion (figure 2.5). It is
also called a uniport transport.
Example of facilitated diffusion is
glucose transport in muscle and
adipose cells is carrier-mediated,
according to the electrochemical Figure 2.5: Facilitated diffusion.
gradient, and is inhibited by sugars such
as galactose. Therefore, it is categorized as facilitated diffusion. In diabetes mellitus,
glucose uptake by the muscles and adipose cells is impaired because the carriers for
facilitated diffusion of glucose require insulin.

Simple diffusion Facilitated diffusion

[B] Active
Diffusion according to Same
electrochemical gradient

Energy is not required Same

Does not require a carrier Requires a carrier protein
protein
Simple diffusion is not Have saturation limited (Tm)
saturable
Bidirectional transport Uniport transport

transport: When the carrier-mediated transport occurs against electrochemical

gradient, the process requires energy and is referred to as active transport. Active
transport can be divided into two types:
(i) Primary active transport: In which high energy phosphate compound, ATP,
provides directly the energy required for the transport process (figure 2.6). Such
transports are Na+-K+-ATPase pump, H+ATPase pump (proton pump), H+/ K+-ATPases,
and Ca2+-ATPase pump.

Figure 2.6: Primary active transport.

(ii) Secondary active transport: In which the transport of one substances (e.g. Na +)
accodrding to electrochemical gradient provides the energy to transport another
substance against its electrochemical gradient (figure 2.7). The metabolic energy is not
provided directly, but indirectly from the Na+ gradient, which is maintained across cell
membranes by Na+-K+ ATPase pump. Thus, inhibition of Na+-K+ ATPase

pump will decrease transport of Na + out of cell, decrease the transmembrane Na +

gradient, and eventually inhibit secondary active transport.
Figure 2.7: Secondary active transport.
 The following figure 2.8 summarizes the main types of transport of substances

across the cell membrane:

Figure 2.8: The main types of
transport of substances across the
cell membrane.
[5] Transport of proteins and other large molecules by cytosis: Cytosis is a completely
different type of active transport involving the formation of membrane-bound vesicles
with a diameter of 50–400 nm. Vesicles are either pinched off from the plasma
membrane (exocytosis) or incorporated into it by invagination (endocytosis). Cytosis in
general has three characteristics:

1. It is associated with the expenditure of ATP (active processes).

2. All forms of cytosis involve the formation of protein-coated vesicles with some
exceptions.
3. All are mediated by membrane receptors.
Protein-coated vesicles provide the main route for endocytosis of solids,
macromolecules, and fluids. The surface receptors accumulate at specific depressions at
the cell membrane where its cytosolic surface of it is covered with a coat of protein
called clathrin (figure 2.9). This cell membrane depression is known as coated pits. The
coated pits progressively encloses the substance to be taken into the cell and pinch off
continually to form endocytic vesicles, providing the cell with a mechanism for rapid
internalization of a large amount of a specific molecule without the need to endocytose
large volumes of extracellular fluid.
 Figure 2.9: Receptor-mediated endocytosis.

Endocytosis is of three types: Based on the nature and quantity of material taken up
and the means of uptake, three types of endocytosis that use clathrin coated vesicles
are recognized: phagocytosis, pinocytosis, and receptor-mediated endocytosis.
[A] Phagocytosis (cell eating) is the ingestion of large particles or
microorganisms that occurs in specialized immune cells. An important
function of macrophages in humans is to remove invading bacteria. It occurs
only after the extracellular particle has bound to the extracellular surface
receptors. The particle is then enveloped by expansion of the cell membrane
around it. This vesicle then fuses with many lysosomes, whereupon
lysosomal enzymes digest its contents.
[B] Pinocytosis (cell drinking) is a general term for a nonspecific
process in which a region of the plasma membrane is pinched off to form an
endocytic vesicle inside the cell. During vesicle formation, some fluid and
dissolved solutes from the extracellular medium are trapped inside the
vesicle and internalized by the cell. It occurs in almost all cells and it occurs
continually and specific stimuli are not required.
[C] Receptor-mediated endocytosis Receptor-mediated endocytosis
is a highly selective mechanism by which cells take up a variety of important
molecules, including hormones; growth factors; and serum transport
proteins, such as transferrin (an iron carrier). Foreign substances, such as
diphtheria toxin and certain viruses, also enter cells by this pathway. The
receptors-mediated endocytosis also aids the cellular uptake of molecules
present at low concentrations outside the cell.
Familial Hypercholesterolemia: The significance of LDL receptors and receptor-
mediated endocytosis is illustrated by a hereditary disease called familial
hypercholesterolemia. People with this disease have an abnormally low number of LDL
receptors. Their cells therefore absorb less cholesterol than normal, and the
cholesterol remains in the blood. Their blood cholesterol levels may be as high as 1,200
mg/dL, compared to a normal level of about 200 mg/dL. People who inherit the gene
from both parents typically have heart attacks before the age of 20 (sometimes even in
infancy) and seldom survive beyond the age of 30.
Exocytosis refers to a process reverse to endocytosis. Many cells synthesize
important macromolecules that are exported from the cell. These molecules are
synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, and packed
inside transport vesicles. The vesicles move to the cell surface, fuse with the cell
membrane, and release their contents outside the cell. During exocytosis, the vesicular
membrane is incorporated into the plasma membrane. In this way, cell membranes can
be conserved and reused. An increase in the intracellular Ca2+ concentration (as a
result of cell surface signal such as binding of a hormone to a membrane receptor or a
change in membrane voltage) is a key event that triggers regulated exocytosis.
Exocytosis accounts for hormone secretion, neurotransmitter release, mucus secretion,
and in some cases, ejection of wastes.

The Na+-K+-ATPase pump: The Na+-K+-ATPase is a highly-conserved integral membrane

protein that is expressed in virtually all cells of higher organisms. As one measure of
their importance, it has been estimated that roughly 25% of all cytoplasmic ATP is
hydrolyzed by sodium pumps in resting humans. In nerve cells, approximately 70% of
the ATP is consumed to fuel sodium pumps.

The functions of Na+/K+-ATPase:

1. Helps in maintaining resting membrane potential: The sodium-potassium pump
moves 3 sodium ions out and moves 2 potassium ions in, thus, in total, removing one
positive charge carrier from the intracellular space. Decreasing the activity of Na +/ K+-
ATPase leads to Na+ enters the cell and K + leaves the cell, the concentration gradients
across the cell membrane are dissipated and the cell membrane loses its polarized
state.
2. Helps in transport of ions and substances through cell membrane: Export of
sodium from the cell provides the driving force for several secondary active
transporters membrane transport proteins, which import glucose, amino acids, and
other nutrients into the cell by use of the sodium gradient. Therefore, Na +-K+ pump
provides a Na+ gradient that is used by certain carrier processes.
3. Regulate cellular volume: The sodium-potassium pump (Na+/K+-ATPase)
maintains a low intracellular Na + concentration. Decreasing the activity of Na +/K+-
ATPase leads to an accumulation of intracellular Na +. The osmotic activity of the
increased intracellular Na+ pulls water into the cell, causing the cell to swell.

Regulation of Na+/K+-ATPase:
1. cAMP: The Na+/K+-ATPase is up-regulated by cAMP. Thus, substances causing an
increase in cAMP up-regulate the Na +/K+-ATPase. In contrast, substances causing a
decrease in cAMP down-regulate the Na +/K+-ATPase. Activation of protein kinase A
by cAMP directly phosphorylates the pump and causes a conformational change of
the pump and increases its affinity for intracellular sodium.
2. [Na]i and [K]o: The activity of Na+/ K+-ATPase pump is stimulated by its own substrate,
i.e. by increased intracellular sodium and extracellular potassium concentrations.
3. Exogenous substances: The Na+-K+-ATPase can be pharmacologically modified by
administrating drugs exogenously. For instance, Na+-K+-ATPase found in the
membrane of heart cells is an important target of cardiac glycosides (for example
digoxin and ouabain), inotropic drugs used to improve heart performance by
increasing its force of contraction. Muscle contraction is dependent on the Ca 2+
release from the muscle cells' sarcoplasmic reticulum. Immediately after muscle
contraction, intracellular Ca2+ is quickly returned to its normal concentration by a
carrier enzyme in the plasma membrane, and a calcium pump in sarcoplasmic
reticulum, causing the muscle to relax. Since this carrier enzyme (Na +-Ca2+ counter-
transport, exchanger) uses the Na gradient generated by the Na +-K+ pump to remove
Ca2+ from the intracellular space, slowing down the Na +-K+ pump results in a
permanently elevated Ca2+ level in the muscle, which may be the mechanism of the
long-term inotropic effect of cardiac glycosides such as digoxin.
4. Muscle inactivity and low dietary potassium intake: Muscle inactivity and low
dietary potassium intake decrease the abundance of pump in skeletal muscle, and
vice versa. Accumulation of potassium in the interstitium of skeletal muscle during
repetitive action potential depolarizes membrane potentials and contributes to
muscle fatigue. Up-regulation of Na+, K+-ATPase will enhance muscle potassium
uptake and reduce potassium accumulation in the interstitium during exercise, and
explain why physical training increases exercise endurance. Up- and down-regulation
of Na+, K+-ATPase are important in maintaining extracellular potassium homeostasis
in response to high and low dietary potassium intake, respectively.
5. Hormones: Major hormonal controls over pump activity can be summarized as
follows:
• Thyroid hormones appear to be a major player in maintaining steady-state
numbers of pumps in most tissues. This effect appears to result from stimulation of
gene transcription.
• Aldosterone is a steroid hormone with major effects on sodium homeostasis. It
stimulates both rapid and sustained increases in pump numbers within several tissues.
The sustained effect is due to enhanced transcription of the genes.
• Catecholamines have varied effects, depending on the specific hormone and
tissue. For example, dopamine inhibits Na+-K+-ATPase activity in kidney, while
epinephrine stimulates pump activity in skeletal muscle. These effects seem to be
mediated via phosphorylation or dephosphorylation of the pumps.
• Insulin has multiple effects on sodium pump activity. Within minutes of elevated
insulin secretion, pumps have increased affinity for sodium, up-regulation of pump
activity through activation of adenylate cyclase to produce cAMP. In skeletal muscle,
insulin may also recruit pumps stored in the cytoplasm or activate latent pumps already
present in the membrane.

Formation of Interstitial Fluid and Lymph

Formation of interstitial fluid: Exchange of water and dissolved substances through
capillary wall depends upon the type of capillary. In general, three types of capillaries
have been described.
Type 1 or Continuous capillaries: These capillaries have uninterrupted membranes and
they only allow smaller molecules, such as water and ions to pass through their
intercellular clefts. However lipidsoluble molecules can passively diffuse through the
endothelial cell membranes along concentration gradients. They occur in skin, muscle,
pulmonary circulation, nervous system, connective and adipose tissue.
Type 2 or Fenestrated capillaries: These capillaries have fenestrated membranes.
Fenestrations are being of the order of 0.1 micrometer. The extremely thin fenestral
membrane confers a very high permeability to water and to small lipophobic solutes,
and limited amounts of protein. They are found in tissues specialized for water
exchange, including all the exocrine glands, e.g. salivary glands, pancreas.
Typical sites are glomeruli of the kidneys and intestinal epithelium.
Type 3 or Discontinuous (sinusoidal) capillaries: Capillaries have discontinuous
membranes. They are interrupted by large intercellular spaces through which fluids and
cells can pass. These capillaries are found in the bone marrow, spleen and liver.
The primary factors (Starling forces) that determine fluid movement through the
capillary membrane: Starling proposed that fluid exchange across the capillary wall
between plasma and interstitial fluid was achieved by a balance between four forces, in
addition to capillary permeability. These forces include (figure 2.10):
[1] The capillary hydrostatic pressure, which tends to move or to filter the fluid
outward through capillary membrane. The capillary pressure at the arteriolar end is
about 35 mm Hg and it is about 15 mm Hg at the venous side (except in glomerular
capillaries, where it is higher and nearly constant of about 50-60 mm Hg). The filtration
is greater at the arteriolar side than at the venous side.
[2] The interstitial fluid hydrostatic pressure, which tends to move fluid outward
through the capillary membrane when interstitial fluid pressure is negative. It is about –
4 to – 5 mm Hg. The interstitial pressure can be affected by lymphatic drainage and by
the tissue tension. If the lymphatic drainage is blocked, the interstitial fluid pressure is
increased. Moreover, in palms of the hands and in the muscles, the interstitial fluid is
less able to expand its volume because of the anatomical arrangement of its connective
tissues and therefore is likely to cause an increase in the interstitial fluid pressure. On
the other hand, the loose texture of the connective tissue below the eyes and behind
the wrists is less resistance to an increase in volume of the interstitial fluid.
[3] The plasma colloid osmotic pressure, which tends to cause osmosis of fluid
inward through the membrane. The colloid osmotic (oncotic) pressure of normal
human plasma averages approximately 25 mm Hg mainly is caused by the dissolved
protein (6-8 g/dL). About 75% of the total colloid osmotic pressure of the plasma result
from the albumin fraction, 25% from globulin, and almost non from the fibrinogen. This
is because albumin has a smaller M.W. than others, so there are more molecules per
gm of albumin than molecules per gm of globulin. Moreover, albumin is more
dissociated in plasma than globulin.

[4] The interstitial fluid colloid osmotic Pc = Capillary

pressure due to protein (about 2 g/dL) which tends hydrostatic
to cause osmosis of fluid outward through the pressure (mm
membrane. It is about 6 mm Hg1 The protein Hg) Pi =
concentration is influenced, in part, by the amount Interstitial
of fluid filtration into the interstitium. For example, hydrostatic
increased capillary filtration into the interstitium pressure πc=
decreases interstitial protein concentration and Capillary
reduces the oncotic pressure. oncotic
[5] Capillary permeability: The capillary is pressure (mm
completely permeable to small molecules and
Hg) πi=
water, but is normally only slightly permeable to
Interstitial
plasma protein. This permeability to colloids may be
oncotic
increased by a number of factors such as certain pressure.
poisons, oxygen lack and bacterial toxins.
Therefore, the Starling equation is: Jv = Kf [(Pc-Pi) – Example: At the arteriolar
(πc – πi)]. end of a capillary, Pc is 35 mm
Jv = Fluid movement (ml/min) Hg, π c is .8 mm Hg, Pi is -4 mm
Kf = Capillary permeability (ml/min/mm Hg) Hg, and π i is 1 mm Hg. Will
filtration or absorption occur?
Net pressure (Jv) (35 – [- 4])
– (28 – 6) = + 17 mm Hg.
Because the net pressure is
positive, filtration will occur. If
the net pressure is negative,
absorption will occur.
The hydrostatic pressure is
greater at the arteriolar end
Figure 2.10: The primary
factors (Starling forces) that
determine fluid movement
through the capillary
membrane.
than that at the venous end. The effect of the plasma proteins is to withdraw fluid from
the more dilute interstitial fluid into the highly concentrated plasma. Therefore, at the
arteriolar end the hydrostatic pressure is greater than the osmotic pressure and water
and salts pass from the plasma to the interstitial fluid, while at the venous end the
hydrostatic pressure is lower than the osmotic pressure and water and salts pass from
interstitial fluid to the plasma. In this way a dynamic equilibrium is set up by water
passing from the plasma to the lymphatic.

Formation of lymph: Lymphatics form a closed system of tubes consisting of

endothelial lining supported by fibrous tissue. Out of the filtered fluid from the capillary
10% enters in these lymphatics whereas 90% is reabsorbed at the venous end.
Lymphatics are much more permeable to proteins than capillaries. The proteins leaked
from plasma into interstitial space cannot return to capillary because of adverse
concentration gradient. Their accumulation in interstitial space will upset starling
equilibrium and proteins diffuse into the very permeable lymphatic capillaries together
with large molecules produced by cells such (as hormones, enzymes, lipoproteins,
chylomicrons). Large lymphatics have muscle fibers in their walls, lymphatic vessels
possess numerous valves and the flow of lymph from periphery to thoracic duct and
right lymphatic duct is brought about by muscular and respiratory movement in the
same way as blood flows in the veins. Right lymphatic duct opens in right subclavian
vein and thoracic duct opens in left subclavian vein. The lymphatics of intestine
(lacteals) show rhythmic contraction which, because of the many valves propel lymph
into the thoracic duct. This contractile activity is an intrinsic property of the lymphatics
and is not coordinated by NS.

Lymph:
1. Has same concentration of salts as interstitial fluid and plasma.
2. Has lower concentration of proteins than plasma.
3. Has slightly higher concentration of proteins than interstitial fluid. This is because the
lymph before reaching the blood lymph passes through at least one or more (usually
8-10) lymph nodes. During its passage through a lymph node the lymph is altered in
composition by: i. Newly formed antibodies (immunoglobulins) are added.
ii. Lymphocytes enter.

Main functions of Lymph:

1. Return of proteins to blood from tissue spaces.
2. Fat from intestine are mainly absorbed through lymph.
3. Maintain fluid distribution in body.

Edema: Disturbance of water balance in which there is an excess of fluid in tissue

spaces and serous cavities of the body is called edema. Edema is detectable clinically
only when the interstitial fluid volume is increased by at least 10%. The factors that
cause edema are:

• Increase in capillary hydrostatic pressure (at arterial or venous side).

• Decrease in plasma oncotic pressure (due to hypoproteinemia) or an increase in
interstitial oncotic pressure (due to an increase of capillaries permeability to
proteins as in case of inflammation, toxins, or other conditions).

• Obstruction of lymphatic drainage (lymphedema, which is an edema of a part of

the body due to complete obstruction of lymphatic vessel draining from such
part).

However, experimental and clinical observations indicate that edema does not
occur until there is a relatively large change in one of these parameters. This is because
the body has protective mechanisms against the development of edema.

Protection factors against edema:

• An increase in lymphatic flow: Lymphatic flow is able to increase as the interstitial
fluid volume is increased, so that the excess filtrate can initially be carried away.
• As fluid initially moves into the interstitium from capillaries, the interstitial oncotic
pressure will fall (both by dilution and by the lymphatic removal of interstitial
proteins), thereby minimizing the gradient for further entry of water from
capillaries into the interstitium.
• The increase in interstitial fluid volume will cause the interstitial hydrostatic
pressure to rise; edema cannot occur until the normally negative value of
interstitial space becomes positive.
The importance of these safety factors varies from organ to organ. In skeletal muscle,
for example, all three contribute. In comparison, the hepatic sinusoids are relatively
open and freely permeable to proteins. As a result, there is normally no oncotic
pressure gradient across the sinusoids, since the plasma and interstitial oncotic
pressures are roughly equal. Thus, the hydrostatic pressure gradient is unopposed,
although the intrasinusoidal pressure is relatively low because most of the hepatic
perfusion derives from the low-pressure portal venous system. In this setting, it is
hepatic lymph flow that is primarily responsible for preventing the accumulation of
excess interstitial fluid.