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OXYGEN & CARBON DIOXIDE TRANSPORT BY BLOOD

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OXYGEN & CARBON DIOXIDE TRANSPORT BY BLOOD

General Goal To describe the storage of oxygen and carbon dioxide in blood and tissues, and to provide a framework for understanding how these stores interact.




Specific Objectives The student should:

be able to name the major regions of drop as blood moves from alveolus to mitochondria.

know the shape of the myoglobin dissociation curve, and be able to state the two major functions of myoglobin.

know what is meant by the P50 of hemoglobin, be able to sketch a normal oxygen dissociation curve, and be able to state the significance of the flat portion for oxygen loading, and the steep portion for oxygen unloading.

be able to define oxygen carrying capacity, oxygen content, oxygen saturation, and oxygen partial pressure.

be able to describe the effects of pH, 2,3-DPG, temperature , and on hemoglobin P50.

be able to describe the effects of methemoglobinemia, carboxyhemoglobin, and anemia on oxygen carrying capacity.

be able to define the Bohr effect, the Haldane effect, and the chloride shift.

be able to quantitate the way in which CO2 is carried in plasma and the red cells.

be able to describe the significant differences between the oxygen dissociation curve and the carbon dioxide dissociation curve.

Resources Lecture: Dr. Baer

Reading: West, JB. Respiratory Physiology-The Essentials (4th Ed.). Chapter 6.

Mines, AH. Respiratory Physiology. Raven Press. Chapters 4, 5, & 6.

I.           OXYGEN TENSIONS FROM ALVEOLI TO MITOCHONDRIA

Figure 1. The transport of oxygen in higher organisms requires the presence of concentration gradients at several sites, with the oxygen tension progressively falling from the lung alveoli to the mitochondria in the peripheral tissues where oxygen is consumed.

A.         Although oxygen tension falls in several places, the greatest fall in oxygen tension occurs across the systemic capillaries.

B.         Mixed venous is normally 40 mmHg.

Some tissues extract a greater proportion of oxygen from arterial blood and have a .

Some tissues extract a lesser proportion of the oxygen from arterial blood and have a .

C.         The partial pressure of oxygen in the mitochondria is often considerably lower than the at the end of the systemic capillary. It is therefore unfair to use the of an organ as a measure of its cellular .

D.         Diffusion-limited transport. The existence of an end-capillary gradient in some peripheral tissues is indicative of diffusion limited transport.

E.          The total body oxygen stores include:

oxygen in the cells.

oxygen in the blood.

oxygen in the lung.

II.        CELLULAR OXYGEN STORES AND MYOGLOBIN

A.         Cells without myoglobin have oxygen stores limited by oxygen’s solubility.

B.         Myoglobin is a protein which binds oxygen in red muscle. Red muscle includes the heart which is a continuously working aerobic organ and red skeletal muscle used in the performance of aerobic or endurance exercise.

C.         Myoglobin Functions. There are 2 probable functions.

Buffer changes in tissue during changes in cellular metabolism.

Facilitate O2 diffusion through the cytoplasm to the mitochondria where the O2 is used.

D.         Myoglobin dissociation curve.

Figure 2

Myoglobin is a single polypeptide chain containing 1 heme group. Each molecule of myoglobin binds one molecule of O2.

Myoglobin binding kinetics obey simple mass action laws and are therefore Michaelis-Menton kinetics.

The P50 of myoglobin is the partial pressure at which 50% of the myoglobin molecules (or 50% of the myoglobin binding sites) have bound O2. This is by analogy to the Km of an enzyme.

At venous levels, myoglobin is nearly fully saturated.

At mitochondrial levels, a small fall in causes myoglobin to release most of its oxygen for use (steep part of curve).

E.          Myoglobin is also thought to facilitate intracellular O2 transport.

Figure 3. The presence of myoglobin can facilitate diffusion within a cell. If the concentration gradient of O2 is in a range over which the concentration of oxygen greatly affects the degree of its binding to myoglobin, much more of the myoglobin will be oxygenated on the high side of the gradient. Effective concentration gradients will therefore be established for oxymyoglobin (MbO2) in one direction and for deoxymyoglobin (Mb) in the opposite direction, so that molecules of the carrier will go to and fro across the concentration gradient, picking up O2 on the high side, and releasing it on the low.

III.     BLOOD OXYGEN STORES AND HEMOGLOBIN

A.         Oxygen is carried in blood in 2 forms

Dissolved in plasma. Normally insignificant.

Bound to hemoglobin in red blood cells.

B.         Ways of expressing the amount of oxygen in blood.

O2 Partial Pressure. (Also called oxygen tension.) Units are mmHg. The partial pressure of oxygen is proportional to the amount of O2 dissolved in blood. Partial pressure differences are of significance in determining the rate of diffusion between blood and tissue.

O2 Content. Units are ml O2/dl blood. These are often written ml/dl. An older synonym is Vol%. By convention volume units are substituted for molar units (moles/liter) although the later could be calculated by the gas law. O2 content is the total amount of oxygen in a deciliter of blood and includes both dissolved and hemoglobin-bound oxygen, but dissolved [Hb] is normally negligable. Ignoring dissolved Hb:

O2 Saturation. This is the fraction or percentage of all the hemoglobin binding sites that are currently occupied by oxygen. Units are usually percent.

Since dissolved O2 content is normally negligible, saturation can be thought of as content/capacity.

C.         Dissolved O2. The arterial plasma normally contains:

D.         Hemoglobin contains 2 alpha chains and 2 beta chains each of which contains 1 heme group. One molecule of hemoglobin can bind 4 molecules of O2.

One g of hemoglobin can bind 1.36 ml O2. (The numbers 1.34 ml O2 and 1.39 ml O2 are also in common use.)

Blood normally contains 15 g/dl of hemoglobin.

From above, the oxygen binding capacity of blood with a normal hemoglobin is:



E.          When breathing 100% O2 dissolved O2 contributes 1.8 ml O2/dl blood.

Figure 4. O2 dissociation curve (solid line) for pH 7.4 PCO2 40 mmHg and 37°C. The total blood O2 content is also shown for a hemoglobin concentration of 15 g/100 ml of blood.

F.          Sigmoid binding curve. Cooperativity causes the oxygen dissociation curve to display sigmoid kinetics.

The Hill coefficient is 2.8 (not the expected 4) because cooperativity is not complete.

The P50 for hemoglobin (half the binding sites saturated) is 27 mmHg as opposed to 2.8 mmHg for myoglobin.

If there were no cooperativity (Hill coefficient of 1) and a P50 = 27 mmHg, then hemoglobin would take up less O2 at the lungs (only 79% saturated at ) and would give up less O2 as fell to venous levels.

G.         Significance of the Sigmoid curve

Figure 5. Oxygen-hemoglobin dissociation curve. The “driving” pressure for loading O2 onto Hb is arterial O2 tension, which is represented by the amount of O2 physically dissolved in solution: a = arterial; v = venous; P50 = O2 tension required to saturate 50% of the hemoglobin.

Hemoglobin is 90% saturated even when arterial falls to 60 mmHg. This is because the upper portion of the curve is relatively flat.

In systemic capillaries where blood may be low hemoglobin becomes desaturated, i.e., it releases oxygen for uptake by cells. This is the steep portion of the curve.

Normally hemoglobin gives up less than half its O2. There is reserve in the system. If systemic capillary falls further (eg. in exercise) there is plenty of additional O2 available from hemoglobin.

H.         Tabular oxygen dissociation curve (*remember these to sketch your own)

*Values needed reasonably accurate dissociation curve. Remember that the PO2 at which the saturation is 50% (the P50, detailed later) 27 mmHg.

Blood

%O2 Saturation

IV.      CHANGES IN HEMOGLOBIN AFFINITY FOR OXYGEN

A.         Changes in hemoglobin affinity for oxygen result in a change in P50. Note that the maximum oxygen capacity is not changed. (change in Km not Vmax.)

Figure 6

Increased hemoglobin affinity for O2. The oxygen dissociation curve shifts to the left. P50 is reduced.

Decreased hemoglobin affinity for O2. The oxygen dissociation curve shifts to the right. P50 is increased.

B.         Shifts in oxyhemoglobin dissociation curve have minimal effects on oxygen loading in the lung because the oxygen dissociation curve is still fairly flat at a of 100 mmHg.

C.         Shifts in the oxyhemoglobin dissociation curve have a maximal effect on oxygen unloading at the tissues because the curve is steep at venous (eg. 40 mmHg).

D.         Hydrogen Ion. Increased [H+] (decreased pH) increases the P50 (decreased O2 affinity) and shifts the dissociation curve to the right. Decreasing [H+] the opposite effect.

Figure 7

Acidosis promotes oxygen unloading. At compare at pH = 7.4 with at pH = 7.2.

Alkalosis inhibits oxygen unloading.

E.          Carbon dioxide (Bohr Effect). Increasing increases P . Decreasing decreases P

Figure 8

The major portion of the Bohr Effect is due to the fact that increasing causes a decreased red cell pH (acidosis).

A secondary part of the Bohr Effect is due to the fact that CO2 reacts covalently with hemoglobin to form carbamino hemoglobin which has a reduced O2 affinity.

The Bohr Effect plays a significant role in oxygen unloading under normal, physiological conditions. The P50 of a “venous” oxygen dissociation curve may be as high as 35 mmHg as compared to the normal arterial value of 27 mmHg.

F.          Temperature. Increasing temperature increases P50. Decreasing temperature decreases P50.



Figure 9

G.         Exercise. Increase temperature, increased and decreased pH all promote oxygen unloading at the tissues by increasing P50 (decreased affinity).

H.         2,3-diphosphoglycerate (2,3-DPG). 2,3-DPG is a glycolytic intermediate which accumulates to uniquely high levels in red cells. Increased levels increase P50; decreased levels decrease P50. Increased levels occur in association with hypoxia.

Increased levels of 2,3-DPG may be seen in:

a)          acclimatization to high altitudes.

b)          chronic lung disease; emphysema.

c)          anemia.

d)          hyperthyroidism.

e)          right to left cardiac shunt.

f)            congenital heart disease.

g)          pulmonary vascular disease.

Blood bank storage. Blood storage in citrate-phosphate-dextrose solution for as short as 1 week can lead to significant 2,3-DPG depletion and left-shifted oxygen dissociation curves.

Fetal hemoglobin. 2,3-DPG levels do not affect the P50 of fetal hemoglobin.

V.         CHANGES IN O2 CARRYING CAPACITY OF HEMOGLOBIN

A.         Hemoglobin Concentration. Hemoglobin concentration will change from its normal value of 15 g/dl as hematocrit changes.

Figure 10

Anemia will decrease the oxygen carrying capacity of blood without independently altering the P50 of blood.

Polycythemia will increase the oxygen carrying capacity of blood without independently altering the P50 of blood.

B.         Carbon Monoxide. Carbon monoxide binds hemoglobin at the oxygen binding sites to form carboxyhemoglobin. It has approximately 210 times the affinity of oxygen.

Figure 11.—Dissociation curves for HbO2 and HbCO. Dissociation curves are plotted on the same scale. Maximal saturation of hemoglobin with O2 is not reached until the PO2 is greater than 120 mmHg; with CO, however, maximal saturation is attained with PCO of less than 1 mmHg.

Occupation of binding sites by CO effectively eliminates them for O2 binding and therefore reduces O2 binding capacity (see figure in Section A above).

Because of the complex cooperativity between hemoglobin subunits, binding of some sites by CO also reduces P50 for oxygen binding. Note that this does not occur with anemia.

C.         Methemoglobin. The heme groups of hemoglobin normally contain ferrous iron (Fe++) whether bound to oxygen or not.

Oxidizing Agents. Certain drugs and chemicals (eg. nitrates, acetanilide, sulfonamides) can oxidize the heme Fe++ to Fe+++. The resulting hemoglobin is called methemoglobin and does not bind O2. The total oxygen carrying capacity is reduced by the amount of hemoglobin that is methemoglobin.

A certain amount of methemoglobin forms spontaneously. This is normally less than 1% of total hemoglobin. The enzyme NADH-methemoglobin reductase helps prevent accumulation of methemoglobin.

VI.      CARBON DIOXIDE STORES

A.         The solubility of carbon dioxide is 0.075 ml CO2/dl/mmHg.

B.         Carbon dioxide is carried in the plasma in two forms.

Dissolved CO2. At the dissolved CO2 concentration is 3.4 ml/dl.

Carbamino compounds. Plasma protein concentration is about 7%. CO2 binds the amine groups of plasma proteins to form carbamino compounds. The hydrogen ions formed are buffered by plasma proteins.

Plasma has little carbonic anhydrase so CO2 forms little carbonic acid in plasma.

C.         Carbon dioxide is carried by the red blood cell in three forms.

Figure 12

Dissolved CO2. CO2 can cross the red cell membrane and dissolve in RBC water.

Carbamino compounds. Approximately 30% of RBC contents is hemoglobin. CO2 can form carbamino hemoglobin on amine groups. The H+ released by this reaction is buffered by histidine residues (imidazole group) on the hemoglobin itself.

Bicarbonate. Carbonic anhydrase is present in RBCs and catalyze the formation of carbonic acid which dissociated to hydrogen ion and bicarbonate. The H+ is buffered by hemoglobin.

D.         Chloride Shift. As is formed it diffuses out of the red cell. Cl- diffuses into the red cell to maintain electroneutrality. This is the Chloride Shift or Hamburger Shift.

The chloride shift is rapid and is complete before the cells exit the capillary.

The osmotic effect of the extra and Cl- in venous red cells causes the venous RBC volume to increase slightly. For this reason venous hematocrit slightly exceeds arterial hematocrit.

E.          Quantitative summary of CO2 transport.

Figure 13

90% of arterial CO2 stores are carried as with 5% of the stores carried as dissolved CO2, and 5% of the stores as carbamino compounds.

Of the CO2 added in systemic capillaries, 60% is added as , 30% is added as carbamino compounds and 10% is added as dissolved CO2.

VII.           CARBON DIOXIDE DISSOCIATION CURVE

A.         The total CO2 content of blood can be plotted as a function of

Figure 14

B.         Haldane effect. Increasing O2 tension decreases the affinity of hemoglobin for CO2. As a result the CO2 “dissociation curve” shifts downward.

High promotes CO2 unloading in the lungs.

Low promotes CO2 loading in the periphery.

C.         Comparison of CO2 and O2 dissociation curves.



Figure 15

CO2 content is far higher than O2 content at physiological partial pressures.

The CO2 dissociation curve is approximately linear (a straight line) in the range of arterial and venous blood. Thus, if equal volumes of blood of 2 different CO2 contents are mixed together, the resulting will be half way between the starting values.

The O2 dissociation is curved between arterial and venous points. Thus, if equal volumes of blood of 2 different O2 contents are mixed together, the resulting blood will have a which is not centered between the original values.

VIII.        CARBON DIOXIDE AND ACID-BASE BALANCE

A.         The lungs excrete 13,000 mEq a day of CO2 representing an equivalent volume of carbonic acid. The kidneys excrete 40-80 mEq/day fixed acid.

B.         Henderson-Hasselbach Equation

C.         Changes in cause changes in [H+] by mass action.

An increase in results in respiratory acidosis.

An decrease in results in respiratory alkalosis.

D.         The effect of altered on pH depends on whether the bicarbonate buffer system acts alone or in concert with other buffer systems.

TABLE 1. Effects of adding CO2 to fluids with and without buffers other than bicarbonate

Type of Fluid

(mEq/liter)

pH

[H+]

(nEq/liter)

(mmHg)

A. Fluid with no nonbicarbonate buffers of importance (CSF)

INITIAL

FINAL

B. Fluid with buffers in addition to bicarbonate (blood)

INITIAL

FINAL

CSF. The bicarbonate buffer system works alone and has a larger effect on pH.

Blood. Hemoglobin buffers H+ changes in addition to Thus, changes in have somewhat blunted effect on pH.

STUDY QUESTIONS FOR OXYGEN AND CARBON DIOXIDE TRANSPORT

What is meant by the term P50?

What is the Bohr Effect? The Haldane Effect?

List four factors which will increase the P50 for hemoglobin. What is the functional significance of an increase P50 (rightward shift in the O2 dissociation curve)?

How will each of the following affect and oxygen content of arterial blood ? a) Anemia; b) Polycythemia; c) Low in inspired air; d) 2,3 DPG; e) Increased ; f) Fever; g) Carbon monoxide poisoning; h) Methemoglobinemia

What effect does oxygen uptake in the lungs have on the buffering capacity of blood? What does oxygen unloading in tissues have?

How does oxygen unloading in tissues affect carbon dioxide uptake by blood?

How does oxygen loading in lungs affect carbon dioxide release from blood?

What role does the chloride shift play in carbon dioxide transport by blood?

In what form is carbon dioxide carried in blood? What is the percent contribution of each?

Calculate the oxygen carrying capacity of a person with hemoglobin concentration of 18 g/dl. What is his approximate arterial saturation if his is 17 ml/dl?

In a normal person, what would be the O2 saturation at a of 40 mmHg? At 27 mmHg? At 60 mmHg?

Of what significance is the fact that the CO2 dissociation curve is linear over the normal range? Hint: how does this affect mixing of blood?






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