Diffusion of Gases Through the Respiratory Membrane

Respiratory Unit.
 Respiratory unit (respiratory lobule) is composed of a respiratory bronchiole, alveolar ducts
& alveoli.
 There are about 300 million alveoli in 2 lungs, and each alveolus has an average diameter of
about 0.2mm.
 The alveolar walls are extremely thin, and between the alveoli is an almost solid network of
interconnecting capillaries. Indeed, because of the extensiveness of the capillary plexus, the
flow of blood in the alveolar wall has been described as a “sheet” of flowing blood.
 Thus, the alveolar gases are in very close proximity to the blood of the pulmonary
capillaries.
Respiratory Membrane.
 The following are different layers of the respiratory membrane:
1. A layer of fluid lining the alveolus containing surfactant that reduces surface tension of the
alveolar fluid.
2. The alveolar epithelium composed of thin epithelial cells.
3. An epithelial basement membrane.
4. A thin interstitial space between the alveolar epithelium and the capillary membrane.
5. A capillary basement membrane. 6. The capillary endothelial membrane.
 Despite the large number of layers, the overall thickness of the respiratory membrane in
some areas is as little as 0.2 μm, and it averages about 0.6 micrometer, except where there
are cell nuclei.
 From histological studies, it has been estimated that the total surface area of the
respiratory membrane is about 70 m2 in the normal adult human male.This is equivalent to
the floor area of a 25–by-30–foot room.
 The total quantity of blood in the capillaries of the lungs at any given instant is 60 to 140 ml.
Now imagine this small amount of blood spread over the entire surface of a 25–by-30–foot
floor, and it is easy to understand the rapidity of the respiratory exchange of oxygen and
carbon dioxide.
 The average diameter of the pulmonary capillaries is only about 5 μm, which means that
red blood cells must squeeze through them. The red blood cell membrane usually touches
the capillary wall, so that oxygen and carbon dioxide need not pass through significant
amounts of plasma as they diffuse between the alveolus and the red cell. This, too,
increases the rapidity of diffusion.

Factors Affecting Rate of Gas Diffusion Through Respiratory Membrane

 The factors that determine how rapidly a gas will pass through the membrane are (1)
thickness of the membrane, (2) surface area of the membrane, (3) diffusion coefficient of
the gas in the substance of the membrane, and (4) the partial pressure difference of the gas
between the two sides of the membrane.
 The thickness of the respiratory membrane occasionally increases as a result of edema (fluid
in the interstitial space of the membrane and in the alveoli) so that the respiratory gases
must then diffuse not only through the membrane but also through this fluid. Pulmonary
fibrosis can increase the thickness of some portions of the respiratory membrane. Because
the rate of diffusion through the membrane is inversely proportional to the thickness of the
membrane, any factor that increases the thickness to more than two to three times normal
can interfere significantly with normal respiratory exchange of gases.
 The surface area of the respiratory membrane can be greatly decreased by many
conditions. Removal of an entire lung decreases the total surface area to one half normal.
Also, in emphysema, many of the alveoli coalesce, with dissolution of many alveolar walls.
Therefore, new alveolar chambers are much larger than the original alveoli, but the total
surface area of the respiratory membrane is often decreased as much as fivefold because of
loss of the alveolar walls. When the total surface area is decreased to about one third to
one fourth normal, exchange of gases through the membrane is impeded to a significant
degree, even under resting conditions, and during competitive sports and other strenuous
exercise, even the slightest decrease in surface area of the lungs can be a serious detriment
to respiratory exchange of gases.
 The diffusion coefficient for transfer of each gas through the respiratory membrane
depends on the gas’s solubility in the membrane and, inversely, on the square root of the
gas’s molecular weight. Therefore, for a given pressure difference, carbon dioxide diffuses
about 20 times as rapidly as oxygen. Oxygen diffuses about twice as rapidly as nitrogen.
 The pressure difference across the respiratory membrane is a measure of the net tendency
for the gas molecules to move through the membrane. When the partial pressure of a gas in
the alveoli is greater than the pressure of the gas in the blood, as is true for oxygen, net
diffusion from the alveoli into the blood occurs; when the pressure of the gas in the blood is
greater than the partial pressure in the alveoli, as is true for carbon dioxide, net diffusion
from the blood into the alveoli occurs.
Diffusing Capacity of the Respiratory Membrane
The ability of the respiratory membrane to exchange a gas between the alveoli and the
pulmonary blood is expressed in quantitative terms by the respiratory membrane’s diffusing
capacity, which is defined as “volume of a gas that will diffuse through the membrane each
minute for a partial pressure difference of 1 mmHg”.
Diffusing Capacity for Oxygen.
 In average young man, diffusing capacity for oxygen under resting conditions averages 21
ml/min/mmHg.
 Mean O2 pressure difference across the respiratory membrane during normal, quiet
breathing is about 11 mmHg. Multiplication of this pressure by the diffusing capacity (11 ×
21) gives a total of about 230ml of O2 diffusing through the respiratory membrane each
minute; this is the rate at which the resting body uses O2.
Change in Oxygen Diffusing Capacity During Exercise.
 During strenuous exercise or other conditions that greatly increase pulmonary blood flow
and alveolar ventilation, diffusing capacity for oxygen increases in young men to a
maximum of about 65 ml/min/mmHg, which is three times the diffusing capacity under
resting conditions.
 This increase is caused by several factors, among which are
(1) Opening up of many previously dormant pulmonary capillaries or extra dilation of
already open capillaries, thereby increasing the surface area of the blood into which the
oxygen can diffuse.
(2) a better match between the ventilation of the alveoli and the perfusion of the alveolar
capillaries with blood, called the ventilation perfusion ratio.
 Therefore, during exercise, oxygenation of the blood is increased not only by increased
alveolar ventilation but also by greater diffusing capacity of the respiratory membrane for
transporting oxygen into the blood.
Diffusing Capacity for Carbon Dioxide.
 Diffusing capacity for CO2 has never been measured because of the following technical
difficulty.
 CO2 diffuses through the respiratory membrane so rapidly that the average Pco2 in the
pulmonary blood is not far different from the Pco2 in the alveoli (less than 1 mmHg) and
with the available techniques, this difference is too small to be measured.
 Because the diffusion coefficient of CO2 is slightly more than 20 times that of oxygen, one
would expect a diffusing capacity for carbon dioxide under resting conditions of about 400-
450 ml/min/mmHg and during exercise of about 1200-1300 ml/min/mmHg.
Measurement of Diffusing Capacity—The Carbon Monoxide Method.
 The oxygen diffusing capacity can be calculated from measurements of,
 (1) alveolar Po2 (2) Po2 in the pulmonary capillary blood (3) the rate of oxygen uptake
by the blood.
 However, measuring the Po2 in the pulmonary capillary blood is so difficult and so imprecise
that it is not practical to measure oxygen diffusing capacity by such a direct procedure.
 Physiologists usually measure carbon monoxide diffusing capacity instead and then
calculate the oxygen diffusing capacity from this. The principle of the carbon monoxide
method is the following:
 A small amount of carbon monoxide is breathed into the alveoli, and the partial pressure of
the carbon monoxide in the alveoli is measured from appropriate alveolar air samples.
 The carbon monoxide pressure in the blood is essentially zero, because hemoglobin
combines with this gas so rapidly that its pressure never has time to build up. Therefore, the
pressure difference of carbon monoxide across the respiratory membrane is equal to its
partial pressure in the alveolar air sample.
 Then, by measuring the volume of CO absorbed in a short period and dividing this by the
alveolar CO partial pressure, one can determine accurately the carbon monoxide diffusing
capacity.
 To convert CO diffusing capacity to oxygen diffusing capacity, the value is multiplied by a
factor of 1.23 because the diffusion coefficient for oxygen is 1.23 times that for carbon
monoxide. Thus, the average diffusing capacity for carbon monoxide in young men at rest is
17 ml/min/mm Hg, and the diffusing capacity for oxygen is 1.23 times this, or 21
ml/min/mmHg.

Hemoglobin and Oxygen Transport

 If lungs are functioning properly, blood leaving in the pulmonary veins and traveling in the
systemic arteries has a Po2 of about 100mmHg.
 The total O2 content of the blood, however, cannot be derived if only the Po 2 of plasma is
known because the total oxygen content depends not only on the Po 2 but also on the
hemoglobin concentration.
 If Po2 and hemoglobin concentration are normal, arterial blood contains about 20 ml of
O2/100 ml blood.

Hemoglobin
 Most of the O2 in the blood is contained within the RBCs, where it is chemically bonded to
hemoglobin.
 Each hemoglobin molecule consists of four polypeptide chains called globins and four
nitrogen containing, disc-shaped organic pigment molecules called hemes.
 The protein part of hemoglobin is composed of two identical alpha chains, each 141 amino
acids long, and two identical beta chains, each 146 amino acids long.
 Each of the four polypeptide chains is combined with one heme group.
 In the center of each heme group is one atom of iron, which can combine with one
molecule of oxygen.
 One hemoglobin molecule can thus combine with four molecules of oxygen and since there
are about 280 million hemoglobin molecules per RBC, each RBC can carry over a billion
molecules of oxygen.
 Normal heme contains iron in the reduced form (Fe++, or ferrous). In this form, the iron can
share electrons and bond with oxygen to form oxyhemoglobin.
 When oxyhemoglobin dissociates to release oxygen to the tissues, the heme iron is still in
the reduced (Fe++) form and the hemoglobin is called deoxyhemoglobin, or reduced
hemoglobin.
 The term oxyhemoglobin is thus not equivalent to oxidized hemoglobin; hemoglobin does
not lose an electron (and become oxidized) when it combines with oxygen. Oxidized
hemoglobin, or methemoglobin, has iron in the oxidized (Fe+++, or ferric) state.
 Methemoglobin thus lacks the electron to form a bond with O 2 and cannot participate in O2
transport.
 Blood normally contains a small amount of methemoglobin, but certain drugs can increase
this amount.
 In carboxyhemoglobin, another abnormal form of hemoglobin, the reduced heme is
combined with carbon monoxide instead of oxygen. Since the bond with carbon monoxide
is about 210 times stronger than the bond with oxygen, carbon monoxide tends to displace
oxygen in hemoglobin and remains attached to hemoglobin as the blood passes through
systemic capillaries.
 In carbon monoxide poisoning which in severe form results primarily from smoke
inhalation, and in milder forms from breathing smoggy air and smoking cigarettes the
transport of oxygen to the tissues is reduced.
Hemoglobin Concentration
 The oxygen-carrying capacity of whole blood is determined by its concentration of
hemoglobin.
 If the hemoglobin concentration is below normal in a condition called anemia, the oxygen
content of the blood will be abnormally low. Conversely, when the hemoglobin
concentration rises above the normal range as occurs in polycythemia (high RBC count) the
oxygen carrying capacity of blood is increased accordingly. This can occur as an adaptation
to life at a high altitude.
 The production of hemoglobin and RBCs in bone marrow is controlled by a hormone called
erythropoietin, produced by the kidneys. The secretion of erythropoietin and thus the
production of RBCs is stimulated when the amount of oxygen delivered to the kidneys is
lower than normal.
 Red blood cell production is also promoted by androgens, which explains why the
hemoglobin concentration in men is from 1 to 2 g/100ml higher than in women.
The Loading and Unloading Reactions
 Deoxyhemoglobin and oxygen combine to form oxyhemoglobin; this is called the loading
reaction.
 Oxyhemoglobin, dissociates to yield deoxyhemoglobin and free O 2 molecules; this is
unloading reaction.
 The loading reaction occurs in the lungs and the unloading reaction occurs in the systemic
capillaries.
 Loading and unloading can thus be shown as a reversible reaction:
(lungs)
Deoxyhemoglobin + O2 (Tissues) Oxyhemoglobin

 The extent to which the reaction will go in each direction depends on two factors:
(1) Po2 of the environment (2) Affinity, or bond strength, between hemoglobin
and oxygen.
 High Po2 drives the equation to the right (favors the loading reaction); at the high Po 2 of the
pulmonary capillaries, almost all the deoxyhemoglobin molecules combine with oxygen.
 Low Po2 in the systemic capillaries drives the reaction in the opposite direction to promote
unloading. The extent of this unloading depends on how low the Po2 values are.
 Affinity between hemoglobin and O2 also influences the loading and unloading reactions. A
very strong bond would favor loading but inhibit unloading; a weak bond would hinder
loading but improve unloading.
 The bond strength between hemoglobin and oxygen is normally strong enough so that 97%
of the hemoglobin leaving the lungs is in the form of oxyhemoglobin, yet the bond is
sufficiently weak so that adequate amounts of oxygen are unloaded to sustain aerobic
respiration in the tissues.

The Oxyhemoglobin Dissociation Curve

 Blood in the systemic arteries, at a Po2 of 100mmHg, has a percent oxyhemoglobin
saturation of 97% (which means that 97% of the hemoglobin is in the form of
oxyhemoglobin).
 This blood is delivered to systemic capillaries, where O 2 diffuses into cells for aerobic
respiration.
 Blood leaving in the systemic veins is thus reduced in O 2; it has a Po2 of about 40mmHg and
a percent oxyhemoglobin saturation of about 75% when a person is at rest.

 Expressed another way, blood entering the tissues contains 20 ml O 2/100 ml blood, and
blood leaving the tissues contains 15.5 ml O2/100 ml blood.
 Thus, 22%, or 4.5 ml of O2 out of the 20 ml of O2/100ml blood, is unloaded to the tissues.
 A graphic illustration of the percent oxyhemoglobin saturation at different values of Po 2 is
called an oxyhemoglobin dissociation curve.


 Values in this graph are obtained by subjecting samples of blood in vitro to different Po2.
 The percent oxyhemoglobin saturations obtained, however, can be used to predict what the
unloading percentages would be in vivo with a given difference in arterial and venous Po2
values.
 The fig. shows difference between the arterial and venous Po 2 and the percent
oxyhemoglobin saturation at rest. The relatively large amount of oxyhemoglobin remaining
in the venous blood at rest serves as an oxygen reserve. If a person stops breathing, a
sufficient reserve of oxygen in the blood will keep the brain and heart alive for about 4-5
minutes without using cardiopulmonary resuscitation techniques.
 The oxyhemoglobin dissociation curve is S-shaped, or sigmoidal. The fact that it is relatively
flat at high Po2 values indicates that changes in Po 2 within this range have little effect on the
loading reaction. One would have to ascend as high as 10,000 feet, for example, before the
oxyhemoglobin saturation of arterial blood would decrease from 97% to 93%. At more
common elevations, the percent oxyhemoglobin saturation would not be significantly
different from the 97% value at sea level.
 At the steep part of the sigmoidal curve, however, small changes in Po 2 values produce
large differences in percent saturation. A decrease in venous Po2 from 40mmHg to
30mmHg, as might occur during mild exercise, corresponds to a change in percent
saturation from 75% to 58%.
 Since the arterial percent saturation is usually still 97% during exercise, the lowered venous
percent saturation indicates that more oxygen has been unloaded to the tissues. The
difference between the arterial and venous percent saturations indicates the percent
unloading.
 In the preceding example, 97% – 75% = 22% unloading at rest, and 97% – 58% = 39%
unloading during mild exercise. During heavier exercise, the venous Po 2 can drop to
20mmHg or lower, indicating a percent unloading of about 80%.

Effect of pH and Temperature on Oxygen Transport

 In addition to changes in Po2, the loading and unloading reactions are influenced by changes
in the affinity of hemoglobin for oxygen.
 Such changes ensure that active skeletal muscles will receive more O 2 from the blood than
they do at rest.
 This occurs as a result of the lowered pH and increased temperature in exercising muscles.
 The affinity is decreased when pH is lowered and increased when pH is raised; this is called
the Bohr effect.
 When the affinity of hemoglobin for oxygen is reduced, there is slightly less loading of the
blood with oxygen in the lungs but greater unloading of oxygen in the tissues. The net effect
is that the tissues receive more oxygen when the blood pH is lowered.
 Since the pH can be decreased by CO2 (through the formation of carbonic acid), the Bohr
effect helps to provide more oxygen to the tissues when their CO 2 output is increased by a
faster metabolism.
 When oxyhemoglobin dissociation curves are graphed at different pH values, the
dissociation curve is seen to be shifted to the right by a lowering of pH and shifted to the
left by a rise in pH.
 If the percent unloading is calculated (by subtracting the percent oxyhemoglobin saturation
for arterial and venous blood), it will be seen that a shift to the right of the curve indicates a
greater unloading of oxygen.
 A shift to the left, conversely, indicates less unloading but slightly more oxygen loading in
the lungs.
 When oxyhemoglobin dissociation curves are constructed at different temperatures, the
curve moves rightward as the temperature increases.
 The rightward shift of the curve indicates that the affinity of hemoglobin for oxygen is
decreased by a rise in temperature. An increase in temperature weakens the bond between
hemoglobin and oxygen and thus has the same effect as a fall in pH.
 Thus, at higher temperatures, more O2 is unloaded to tissues than would be the case if bond
strength were constant. This effect can significantly enhance delivery of O 2 to muscles that
are warmed during exercise.

Effect of 2,3-DPG on Oxygen Transport

 Mature RBCs lack both nuclei and mitochondria. Without mitochondria they cannot respire
aerobically; the very cells that carry oxygen are the only cells in the body that cannot use it!
 Red blood cells, therefore, must obtain energy through the anaerobic respiration of glucose.
 In the glycolytic pathway, a side reaction occurs in the RBCs that results in a unique product
2,3-diphosphoglyceric acid (2,3-DPG).
 Enzyme that produces 2,3-DPG is inhibited by oxyhemoglobin. When the oxyhemoglobin
concentration is decreased, the production of 2,3-DPG is increased. This increase in 2,3-DPG
production can occur when the total hemoglobin concentration is low (in anemia) or when
the Po2 is low (at a high altitude).
 The bonding of 2,3-DPG with deoxyhemoglobin makes the deoxyhemoglobin more stable.
Therefore, a higher proportion of the oxyhemoglobin will be converted to deoxyhemoglobin
by the unloading of its oxygen. An increased concentration of 2,3-DPG in red blood cells
thus increases oxygen unloading and shifts the oxyhemoglobin dissociation curve to the
right.
Anemia
 When the total blood hemoglobin concentration falls below normal in anemia, each RBC
produces increased amounts of 2,3-DPG.
 A normal hemoglobin concentration of 15 g per 100 ml unloads about 4.5 ml O2 per 100 ml
at rest, as previously described. If the hemoglobin concentration were reduced by half, you
might expect that the tissues would receive only half the normal amount of oxygen (2.25 ml
O2/100 ml).
 It has been shown, however, that an amount as great as 3.3 ml O2/100 ml is unloaded to the
tissues under these conditions. This occurs as a result of a rise in 2,3-DPG production that
causes a decrease in the affinity of hemoglobin for oxygen.
Fetal Hemoglobin
 The effects of 2,3-DPG are also important in the transfer of oxygen from maternal to fetal
blood.
 In an adult, hemoglobin molecules are composed of two alpha and two beta chains.
 Whereas fetal hemoglobin has two gamma chains in place of the beta chains (gamma chains
differ from beta chains in thirty-seven of their amino acids).
 Adult hemoglobin in the mother (hemoglobin A) is able to bind to 2,3-DPG. Fetal
hemoglobin, or hemoglobin F cannot bind to 2,3-DPG, and thus has a higher affinity for
oxygen than does hemoglobin A.
 Since hemoglobin F can have a higher percent oxyhemoglobin than hemoglobin A at a given
Po2, oxygen is transferred from the maternal to the fetal blood as these two come into close
proximity in the placenta.

Muscle Myoglobin
 Myoglobin is a red pigment found exclusively in striated muscle cells. In particular, slow-
twitch, aerobically respiring skeletal fibers and cardiac muscle cells are rich in myoglobin.
 Myoglobin is similar to hemoglobin, but it has one heme rather than four; therefore, it can
combine with only one molecule of oxygen.
 Myoglobin has a higher affinity for oxygen than does hemoglobin, and its dissociation curve
is therefore to the left of the oxyhemoglobin dissociation curve.
 The shape of the myoglobin curve is also different from the oxyhemoglobin dissociation
curve. Myoglobin curve is rectangular, indicating that oxygen will be released only when the
PO2 becomes very low.
 Since the Po2 in mitochondria is very low (because oxygen is incorporated into water here),
myoglobin may act as a “go-between” in the transfer of oxygen from blood to the
mitochondria within muscle cells.
 Myoglobin may also have an oxygen-storage function, which is of particular importance in
the heart. During diastole, when the coronary blood flow is greatest, myoglobin can load up
with oxygen. This stored oxygen can then be released during systole, when the coronary
arteries are squeezed closed by the contracting myocardium.
Carbon Dioxide Transport and Acid-Base Balance
 Carbon dioxide is carried by the blood in three forms:
 (1) as dissolved CO2; carbon dioxide is about 21 times more soluble than oxygen in water,
and about one-tenth of the total blood CO2 is dissolved in plasma.
 (2) as carbaminohemoglobin about one-fifth of the total blood CO2 is carried attached to an
amino acid in hemoglobin (carbaminohemoglobin should not be confused with
carboxyhemoglobin, which is a combination of hemoglobin and carbon monoxide); and
 (3) as bicarbonate ion, which accounts for most of the CO2 carried by the blood.
 CO2 is able to combine with water to form carbonic acid. This reaction occurs in plasma at a
slow rate, but it occurs much more rapidly within the RBCs because of catalytic action of the
enzyme carbonic anhydrase.
 Since this enzyme is confined to RBCs, most of the carbonic acid is produced there rather
than in plasma.
 The formation of carbonic acid from CO2 and water is favored by the high Pco2 found in
tissue capillaries (this is an example of the law of mass action).
carbonic anhydrase
CO2 + H2O H2CO3
high Pco2

The Chloride Shift

 As a result of catalysis by carbonic anhydrase within the RBCs, large amounts of carbonic
acid are produced as blood passes through the systemic capillaries. The buildup of carbonic
acid concentrations within the red blood cells favors the dissociation of these molecules
into hydrogen ions (protons, which contribute to the acidity of a solution) and HCO 3
(bicarbonate), as shown by this equation:
H2CO3 → H+ + HCO3–
 The hydrogen ions (H+) released by the dissociation of carbonic acid are largely buffered by
their combination with deoxyhemoglobin within the RBCs. Although the unbuffered
hydrogen ions are free to diffuse out of the RBCs, more bicarbonate diffuses outward into
the plasma than does H+.
 As a result of the “trapping” of hydrogen ions within the RBCs by their attachment to
hemoglobin and the outward diffusion of bicarbonate, the inside of the red blood cell gains
a net positive charge.
 This attracts chloride ions (Cl–), which move into the RBCs as HCO3– moves out. This is made
possible by the presence of a special bicarbonate-chloride carrier protein in the red cell
membrane that shuttles these two ions in opposite directions at rapid velocities.
 This exchange of anions as blood travels through the tissue capillaries is called the chloride
shift.
 The unloading of oxygen is increased by bonding of H + (released from carbonic acid) to
oxyhemoglobin. This is the Bohr effect, and results in increased conversion of
oxyhemoglobin to deoxyhemoglobin.
 Now, deoxyhemoglobin bonds H + more strongly than does oxyhemoglobin, so the act of
unloading its oxygen improves the ability of hemoglobin to buffer the H + released by
carbonic acid. Removal of H + from solution by combining with hemoglobin (through the law
of mass action), in turn, favors the continued production of carbonic acid and thereby
improves the ability of the blood to transport carbon dioxide.
 Thus, CO2 increases oxygen unloading, and oxygen unloading increases carbon dioxide
transport. When blood reaches the pulmonary capillaries, deoxyhemoglobin is converted to
oxyhemoglobin.
 Since oxyhemoglobin has a weaker affinity for H+ than does deoxyhemoglobin, hydrogen
ions are released within the RBCs. This attracts HCO3– from the plasma, which combines
with H+ to form carbonic acid:
H+ + HCO3– H2CO3
 Under conditions of lower Pco2, as occurs in the pulmonary capillaries, carbonic anhydrase
catalyzes the conversion of carbonic acid to carbon dioxide and water:
carbonic anhydrase
H2CO3 CO2 + H2O
low Pco2
 In summary, the CO2 produced by the cells is converted within the systemic capillaries,
mostly through the action of carbonic anhydrase in the red blood cells, to carbonic acid.
With the buildup of carbonic acid concentrations in the red blood cells, the carbonic acid
dissociates into bicarbonate and H+, which results in the chloride shift. A reverse chloride
shift operates in the pulmonary capillaries to convert carbonic acid to H 2O and CO2 gas,
which is eliminated in the expired breath.
 The Pco2, carbonic acid, H+, and bicarbonate concentrations in the systemic arteries are thus
maintained relatively constant by normal ventilation. This is required to maintain the acid-
base balance of the blood.

Effect of Exercise and High Altitude on Respiratory Function

Changes in ventilation and oxygen delivery during exercise and during acclimatization to a high
altitude help to compensate for increased metabolic rate during exercise and for decreased
arterial Po2 at high altitudes.

Ventilation During Exercise

 As soon as a person begins to exercise, breathing becomes deeper and more rapid to
produce a total minute volume that is many times the resting value. This increased
ventilation is exquisitely matched to the simultaneous increase in O2 consumption and CO2
production by the exercising muscles.
 The arterial blood Po2, Pco2, and pH thus remain constant during exercise.
 The mechanisms responsible for the increased ventilation during exercise are complex.
 Two kinds of mechanisms ‘neurogenic’ and ‘humoral’ have been proposed to explain the
increased ventilation that occurs during exercise.
 Neurogenic mechanisms include the following:
 1) sensory nerve activity from the exercising limbs may stimulate the respiratory muscles,
either through spinal reflexes or via the brain stem respiratory centers, and/or
 (2) input from the cerebral cortex may stimulate the brain stem centers to modify
ventilation. These neurogenic theories help to explain the immediate increase in ventilation
that occurs as exercise begins.
 Rapid and deep ventilation continues after exercise has stopped, suggesting that humoral
(chemical) factors in the blood may also stimulate ventilation during exercise.
 Since the Po2, Pco2, and pH of the blood samples from exercising subjects are within the
resting range, these humoral theories propose that;
 (1) the Pco2 and pH in the region of the chemoreceptors may be different from these values
“downstream,” where blood samples are taken, and/or
 (2) cyclic variations in these values that cannot be detected by blood samples may stimulate
the chemoreceptors. The evidence suggests that both neurogenic and humoral mechanisms
are involved in the hyperpnea, or increased total minute volume, of exercise.
Acclimatization to High Altitude
 When a person from a region near sea level moves to a significantly higher elevation,
several adjustments in respiratory function must be made to compensate for the decreased
Po2 at the higher altitude.
 These adjustments include changes in ventilation, in Hb affinity for oxygen, and in total Hb
concentration.
 At an altitude of 7,500 feet, for example, the Po2 of arterial blood is 69 to 74 mmHg
(compared to 90 to 95 mmHg at sea level). Percent oxyhemoglobin saturation at this
altitude is between 92% and 93%, compared to about 96% at sea level.
 The amount of O2 attached to hemoglobin, and thus the total O2 content of blood, is
therefore decreased.
 In addition, the rate at which oxygen can be delivered to the cells after it dissociates from
oxyhemoglobin is reduced at the higher altitude. This is because the maximum
concentration of oxygen that can be dissolved in the plasma decreases with the fall in Po 2.
 People may thus experience rapid fatigue even at more moderate elevations (5,000-6,000
feet), at which the oxyhemoglobin saturation is only slightly decreased.
 Compensations made by the respiratory system gradually reduce the amount of fatigue
caused by a given amount of exertion at high altitudes.
1. Changes in Ventilation
 At altitudes as low as 1,500 m (5,000 feet), decreased arterial Po 2 stimulates an increase in
ventilation.
 This hypoxic ventilatory response produces hyperventilation, which lowers the arterial Pco2
and thus produces a respiratory alkalosis.
 Within few days total minute volume becomes stabilized at a level 2.5 L/min higher than
that at sea level.
 Hyperventilation at high altitude increases tidal volume, thus reducing the proportionate
contribution of air from the anatomical dead space and increasing the proportion of fresh
air brought to the alveoli.
 This improves the oxygenation of the blood over what it would be in the absence of the
hyperventilation.
 Hyperventilation, however, cannot increase blood Po2 above that of the inspired air. The
Po2 of arterial blood decreases with increasing altitude, regardless of the ventilation.
 In the Peruvian Andes, for example, the normal arterial PO2 is reduced from about 100
mmHg (at sea level) to 45 mmHg. The loading of hemoglobin with oxygen is therefore
incomplete, producing an oxyhemoglobin saturation that is decreased from 97% (at sea
level) to 81%.
 Nitric oxide (NO) is produced in the lungs, and a recent study demonstrated increased NO
concentration in the lungs of chronically hypoxic people who live at high altitude. Since NO
is a vasodilator, this could increase pulmonary blood flow and perhaps thus improve the
oxygenation of the blood in these people.
 Furthermore, NO is loaded onto the protein portion of hemoglobin in the lungs and is
unloaded in the tissue capillaries, where it can cause vasodilation. Therefore, NO produced
in the lungs and carried by hemoglobin to systematic capillaries could promote increased
blood flow and oxygen delivery to tissues.
 Finally, NO bound to sulfur atoms (abbreviated SNOs), in the cysteine groups of hemoglobin
and other proteins, can be transferred from blood to the respiratory control center, where
it stimulates breathing.
 Thus, SNOs may contribute to the hypoxic ventilatory response (increased breathing when
the arterial Po2 is low). All of these mechanisms of NO action would provide partial
compensations for the chronic hypoxia of life at high altitude.
2. The Affinity of Hemoglobin for Oxygen
 Normal arterial blood at sea level unloads only about 22% of its oxygen to the tissues at
rest; the percent saturation is reduced from 97% in arterial blood to 75% in venous blood.
 To compensate for the decrease in oxygen content at high altitude, the affinity of
hemoglobin for oxygen is reduced, so that a higher proportion of oxygen is unloaded.
 This occurs because the low oxyhemoglobin content of red blood cells stimulates the
production of 2,3-DPG, which in turn decreases the affinity of hemoglobin for oxygen.
 At very high altitudes, however, the story becomes more complex.
 In one study, the very low arterial Po2 (28 mmHg) of subjects at Mount Everest stimulated
intense hyperventilation, so that the arterial Pco2 was decreased to 7.5 mmHg. The
resultant respiratory alkalosis (arterial pH greater than 7.7) caused the oxyhemoglobin
dissociation curve to shift to the left (indicating greater affinity of hemoglobin for O 2)
despite the antagonistic effect of increased 2,3-DPG concentrations.
 It was suggested that the increased affinity of hemoglobin for O2 caused by the respiratory
alkalosis may have been beneficial at such a high altitude, since it increased the loading of
hemoglobin with O2 in lungs.
3. Increased Hemoglobin and Red Blood Cell Production
 In response to tissue hypoxia, the kidneys secrete the hormone erythropoietin.
 Erythropoietin stimulates the bone marrow to increase its production of hemoglobin and
red blood cells.
 In the Peruvian Andes, for example, people have a total hemoglobin concentration that is
increased from 15 g per 100 ml (at sea level) to 19.8 g per 100 ml.
 Although the percent oxyhemoglobin saturation is still lower than at sea level, the total
oxygen content of the blood is actually greater—22.4 ml O2/100 ml compared to a sea-level
value of about 20 ml O2 /100 ml.
 Polycythemia (high red blood cell count) increases the viscosity of blood; hematocrits of
55% to 60% have been measured in people who live in the Himalayas, and higher values are
reached if dehydration accompanies the polycythemia. The increased blood viscosity
contributes to pulmonary hypertension, which can cause accompanying edema and
ventricular hypertrophy that can lead to heart failure.