A STUDY GUIDE ON

RESPIRATORY PHYSIOLOGY [Volume 2(A1)]

Lecturer: DR IMAFIDON C.E.

Department of Physiology, College of Health Sciences, Bowen University Iwo, Osun State, Nigeria. 1 IMPORTANT NOTICE

This is a study guide! This material does NOT (in any way) exempts you from personal studies. In addition to our online sessions, you are expected to consult your recommended textbooks and online sources in an attempt to provide answers to the questions asked.

Note: This is a continuation of the information that are provided in the previously uploaded study guide (volume 1). Also, a measure of your PROGRESS is how well you are able to attempt the questions provided at the checkpoint. Good success!

2 HEMOGLOBIN, OXYGEN AND CARBONDIOXIDE TRANSPORT  Introduction: Hemoglobin is essential for the oxygen-carrying capacity of blood. Hemoglobin that is void of oxygen is simply deoxyhemoglobin. In the pulmonary capillary, hemoglobin loads with oxygen to form oxyhemoglobin while oxyhemoglobin unloads its oxygen in the capillaries of the systemic circulation. The ability of hemoglobin to load or unload oxygen is influenced by a lot of factors (take note of these factors). Note: In normal functioning lungs, blood leaving the pulmonary veins and flowing in the systemic arteries has a partial oxygen (PO2) level of about 100 mmHg. This translates to a plasma oxygen concentration of about

0.3 ml O2 per 100 ml blood. However, the total oxygen content of blood cannot be derived if only the PO2 of plasma is known. The total oxygen content of blood depends not only on the PO2 but also on the hemoglobin concentration. 3 HEMOGLOBIN

 In the blood, most of the oxygen is contained within the red blood cells where it is chemically bonded to hemoglobin. Each hemoglobin molecule consists of four polypeptide chains called “globin” and four iron-containing, disc-shaped organic 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 red blood cell, each red blood cell can carry over a billion molecules of oxygen. 4 Figure 1: The structure of hemoglobin. (a.) Three- dimensional structure of hemoglobin showing two alpha and two beta polypeptide chains. (b.) The structural formula of 5 heme. …hemoglobin cont’d

 Normal heme contains iron in the reduced form (Fe2+, or ferrous iron). 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 (Fe2+) 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 (Fe3+, or ferric) state. Methemoglobin thus lacks the electron it needs to form a bond with oxygen and cannot participate in oxygen transport. Blood normally contains only a small amount of methemoglobin, but certain drugs can increase this amount.

6 …hemoglobin cont’d

 In carboxyhemoglobin, another abnormal form of hemoglobin, the reduced heme is combined with carbon monoxide instead of oxygen. Because 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.

7 Percentage Oxyhemoglobin Saturation

 This is the percentage of oxyhemoglobin to total hemoglobin. It is measured in order to assess how well the lungs have oxygenated the blood. The normal value of oxyhemoglobin saturation for arterial blood is about 97%; the remaining percentage comprises varying amount of deoxyhemoglobin, carboxyhemoglobin and methemoglobin.

 Because each hemoglobin type has a unique absorption spectrum (each absorbs visible light differently), the oxyhemoglobin saturation as well as the proportion of these other forms can be measured. This feature gives oxyhemoglobin a tomato juice-red colour, whereas carboxyhemoglobin has a colour that is similar to cranberry juice. The oxyhemoglobin saturation is commonly measured using a pulse oximeter but it can be more precisely measured on a sample of arterial blood using a blood-gas machine. 8 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 red blood cell 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 red blood cells in bone marrow is controlled by a hormone called erythropoietin, produced by the kidneys. The secretion of erythropoietin (and thus the production of red blood cells) 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 is from 1 to 2 g per 100 ml higher in men than in women. 9 Loading and Unloading Reactions

 Deoxyhemoglobin and oxygen combine to form oxyhemoglobin; this is called the loading reaction. Oxyhemoglobin, in turn, dissociates to yield deoxyhemoglobin and free oxygen molecules; this is the unloading reaction. The loading reaction occurs in the lungs and the unloading reaction occurs in the systemic capillaries. Therefore, oxygen loading and unloading can be described as a reversible reaction as shown below;

 The extent to which the reaction will go in each direction depends on two factors:

• the PO2 of the environment and • the affinity, or bond strength, between hemoglobin and oxygen.

10 …loading and unloading reactions cont’d

 High PO2 drives the equation to the right (favors the loading reaction); at the high PO2 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.

 The affinity between hemoglobin and oxygen 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. 11 Oxyhemoglobin Dissociation Curve  Basically, this is a graphical illustration of the percentage hemoglobin saturation at different values of PO2. Blood in the systemic arteries, at a PO2 of 100 mmHg, 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 the systemic capillaries, where oxygen diffuses into the cells and is consumed in aerobic respiration.

 Blood leaving in the systemic veins is thus low in oxygen concentration; it has a PO2 of about 40 mmHg and a percent oxyhemoglobin saturation of about 75% when a person is at rest.

Expressed another way, blood entering the tissues contains 20 ml O2 per 100 ml blood, and blood leaving the tissues contains 15.5 ml O2 per 100 ml blood. Thus, 22%, or 4.5 ml of O2 out of the 20 ml of O2 per 100 ml blood, is unloaded to the tissues. 12 Figure 2: Oxyhemoglobin dissociation curve. 13 FLASH POINTS ON OXYHEMOGLOBIN DISSOCIATION CURVE

 The percentage of oxyhemoglobin saturation and the blood oxygen content are shown at different values of PO2. Notice that the percent oxyhemoglobin decreases by about 25% as the blood passes through the tissue from arteries to veins, resulting in the unloading of approximately

5 ml of O2 per 100 ml of blood to the tissues.

 The oxyhemoglobin dissociation curve is S-shaped, or sigmoidal. The fact that it is relatively flat at high PO2 values indicates that changes in PO2 within this range have little effect on the loading reaction.

 A shift of the curve to the right indicates oxygen unloading while a shift to the left indicates oxygen loading. Some factors are responsible for the shift of the oxyhemoglobin dissociation curve either to the left or right (what are these factors? Identify these factors and explain their effects on the oxyhemoglobin dissociation curve). Hint:temperature e.t.c. 14 …flash points on oxyhemoglobin dissociation curve cont’d

 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 to 5 minutes without using cardiopulmonary resuscitation (CPR) techniques. This reserve supply of oxygen can also be tapped when a tissue’s requirements for oxygen are raised, as in exercising muscles.

15 INHERITED DEFECTS IN HEMOGLOBIN: Sickle-cell anemia and Thalassemia  Sickle cell anemia is a disease that occurs when a person inherits the affected gene from each parent and produces hemoglobin S instead of normal hemoglobin A. Hemoglobin S differs from hemoglobin A in that one amino acid is substituted for another (a valine for a glutamic acid) in the beta chains of hemoglobin, due to a single base change in the DNA of the gene for the beta chains.

 Thalassemia is a group of inherited blood disorders in which there is significantly reduced hemoglobin concentration in the blood. There are basically two broad groups of thalassemia; alpha and beta thalassemia.

…additional note has been provided on your Bowen Shub dashboard 16 Figure 3: Sickle cell anemia. (a.) Normal cells (b.) sickled red blood cells as seen in the scanning electron microscope. 17 CARBON DIOXIDE TRANSPORT

 Carbon dioxide is transported in the blood primarily in the form of − bicarbonate (HCO3 ), which is released when carbonic acid dissociates. Carbonic acid, on the other hand, is produced mostly in the red blood cells as blood passes through systemic capillaries.

 Carbon dioxide is carried by the blood in three forms:

(1.) as dissolved CO2 in the plasma—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, formed when carbon monoxide binds to the heme groups of hemoglobin); and

(3.) as bicarbonate ion, which accounts for most of the CO2 carried by the blood 18 …CO2 transport cont’d  Carbon dioxide is able to combine with water to form carbonic acid. This reaction occurs spontaneously in the plasma at a slow rate, but it occurs much more rapidly within the red blood cells because of the catalytic action of the enzyme “carbonic anhydrase”. Since this enzyme is confined to the red blood cells, most of the carbonic acid is produced there rather than in the plasma. The formation of carbonic acid from CO2 and water is favored by the high PCO2 found in the capillaries of the systemic circulation.

19 Figure 4: Carbon dioxide transport and chloride shift 20 …CO2 transport cont’d Note: Carbon dioxide is transported in three forms: (1.) as dissolved CO2 gas, (2.) attached to hemoglobin as carbaminohemoglobin, and (3.) as carbonic acid and bicarbonate. Percentages indicate the proportion of - CO2 in each of the forms. Notice that when bicarbonate (HCO3 ) diffuses out of the red blood cells, Cl− diffuses in to retain electrical neutrality. This exchange is the chloride shift.  The unloading of oxygen is increased by the 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, in turn, favors the continued production of carbonic acid and thereby improves the ability of the blood to transport carbon dioxide. Thus, carbon dioxide increases oxygen unloading, and oxygen unloading improves carbon dioxide transport. 21 Reserve Chloride Shift

 When blood reaches the pulmonary capillaries, deoxyhemoglobin is converted to oxyhemoglobin. Because oxyhemoglobin has a weaker affinity for H+ than does deoxyhemoglobin, hydrogen ions are released - within the red blood cells. This attracts HCO3 from the plasma, which combines with H+ to form carbonic acid:

Under conditions of lower PCO2, as occurs in the pulmonary capillaries, carbonic anhydrase catalyzes the conversion of carbonic acid to carbon dioxide and water

22 • Carbon dioxide is released from the blood as it travels through the pulmonary capillaries. A “reverse chloride shift” occurs during this time, and carbonic

acid is transformed into CO2 and H2O.

• The CO2 is eliminated in the exhaled air. Sources of carbon dioxide in blood include

(1) dissolved CO2, (2) carbaminohemoglobin, and - (3) bicarbonate (HCO3 ).

Figure 5: The reverse chloride shift in the lungs 23 SUMMARY

 The carbon dioxide 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 H2O 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

24 CHECKPOINTS 1.) Write an essay on the oxygen-carrying capacity of blood.

2.)Differentiate between hemoglobin, oxyhemoglobin, de- oxyhemoglobin, methemoglobin and carboxyhemoglobin.

3.) What is pulse oximeter?

4.) Sickle cell anemia and thalassemia are inherited defects in hemoglobin, discuss.

5.) What is physiological neonatal jaundice?

6.) The oxyhemoglobin dissociation curve is sigmoidal in shape, discuss.

7.) Differentiate between loading and unloading reactions.

8.) Discuss oxygen and carbondioxide transport 25