Lecture 3Lecture 3

Gas exchangeGas exchangeOO22 transport transportCOCO22 transport transport

Gas exchangeGas exchangeIt takes place at a respiratory surface. For It takes place at a respiratory surface. For unicellular organisms the RS is simply the unicellular organisms the RS is simply the cell membranecell membrane, but for a large organisms , but for a large organisms it is the it is the respiratory systemrespiratory system..

In humans, respiratory GE or VIn humans, respiratory GE or VEE is carried is carried out by mechanisms of the lungs. out by mechanisms of the lungs.

The matching of VThe matching of VEE and perfusion is the and perfusion is the critical determinant of GE, and a critical determinant of GE, and a deficiency of excess of Vdeficiency of excess of VEE relative to the relative to the amount of BF amount of BF → either inadequate or wasteful → either inadequate or wasteful respiration.respiration.

Alv are designed for rapid GE. Alv are designed for rapid GE.

Alv are found at the end of the branching bronchioles and so they Alv are found at the end of the branching bronchioles and so they have a good air supply.have a good air supply.

The alv walls are very thin and have a moist surface. They are The alv walls are very thin and have a moist surface. They are covered by a network of capillaries which transport the gases. covered by a network of capillaries which transport the gases.

Blood takes about 1 sec to pass through the lung capillaries. In this Blood takes about 1 sec to pass through the lung capillaries. In this time the blood becomes nearly 100% saturated with Otime the blood becomes nearly 100% saturated with O22 and loses its and loses its excess of COexcess of CO22..

When you breath in the first 150 ml fills the tubes which are outside When you breath in the first 150 ml fills the tubes which are outside the alv (anatomic VD). There is also a functional VD (air in these alv the alv (anatomic VD). There is also a functional VD (air in these alv doesn’t exchange with the blood and is part of the VD).doesn’t exchange with the blood and is part of the VD).

The amount of air reaching the alv with each breath is equal to VT – The amount of air reaching the alv with each breath is equal to VT – VD.VD.

Inspired air contains about 21% OInspired air contains about 21% O22 and 78% N and 78% N22, , almost no COalmost no CO22..

Blood returning to lungs is high in COBlood returning to lungs is high in CO22 and is and is low in Olow in O22. While blood leaving lungs is enriched . While blood leaving lungs is enriched with Owith O22, low in CO, low in CO22..

In pulmonary capillaries, OIn pulmonary capillaries, O22 diffuses into diffuses into capillary blood, while COcapillary blood, while CO22 diffuses into alveolar diffuses into alveolar air.air.

NoteNote; No exchange of gases occurs in heart, ; No exchange of gases occurs in heart, arteries, or arterioles. arteries, or arterioles.

The ratio of COThe ratio of CO22 produced / O produced / O22 consumed is known as consumed is known as RQ.RQ.

OO22 transport transport

OO22 is carried in the blood in 2 forms; is carried in the blood in 2 forms;1) bound to Hb (approx 98.5 %)1) bound to Hb (approx 98.5 %)2) dissolved in the plasma (approx 1.5 %).2) dissolved in the plasma (approx 1.5 %).

The amount of any gas that dissolves in blood is directly proportional to The amount of any gas that dissolves in blood is directly proportional to the partial pressure of the gas and the solubility of the gas. Therefore, the partial pressure of the gas and the solubility of the gas. Therefore, COCO22 = SO = SO22 * PO * PO22 (Henry's law). (Henry's law).

where SOwhere SO22 is the solubility of O is the solubility of O22..

At 37C, the solubility of OAt 37C, the solubility of O22 is 0.003 ml O is 0.003 ml O22 / 100 ml blood / mmHg. The  / 100 ml blood / mmHg. The content of Ocontent of O22 dissolved in blood = 0.003 * PO dissolved in blood = 0.003 * PO22. If plasma PO. If plasma PO22 is 100 mmHg is 100 mmHg (arterial blood), the amount of O(arterial blood), the amount of O22 dissolved is 0.3 ml. This small amount of dissolved is 0.3 ml. This small amount of OO22 will not sustain normal human metabolism. So another method is will not sustain normal human metabolism. So another method is needed to transport Oneeded to transport O22 to tissues in sufficient quantity to meet metabolic to tissues in sufficient quantity to meet metabolic demands. The Hb mol meets this requirement. demands. The Hb mol meets this requirement.

Each mol of Hb can carry 4 mol of OEach mol of Hb can carry 4 mol of O22. Fully sat Hb can carry approx 1.36 . Fully sat Hb can carry approx 1.36 ml Oml O22 / g Hb, and normal human blood contains about 15 g Hb / 100 ml  / g Hb, and normal human blood contains about 15 g Hb / 100 ml blood. Multiplying these two constants yields 20.4 ml Oblood. Multiplying these two constants yields 20.4 ml O22 / 100 ml blood.  / 100 ml blood. Because blood is almost fully sat at a POBecause blood is almost fully sat at a PO22 of 100, there are about of 100, there are about 20 ml O2 / 100 ml of normal arterial blood, which is considerably more 20 ml O2 / 100 ml of normal arterial blood, which is considerably more than the 0.3 ml dissolved in plasma.than the 0.3 ml dissolved in plasma.

Hb is a protein in which a haem group is attached to Hb is a protein in which a haem group is attached to each of 4 subunit polypeptide chain (2 alpha & 2 beta). each of 4 subunit polypeptide chain (2 alpha & 2 beta). Hb contains 4 iron atoms (4 haem group). Each one Hb contains 4 iron atoms (4 haem group). Each one contain a Fecontain a Fe2+ 2+ within a haem group.within a haem group.

If 100 ml of plasma is exposed to an atmos with a POIf 100 ml of plasma is exposed to an atmos with a PO22 of 100 mmHg, only 0.3 ml of Oof 100 mmHg, only 0.3 ml of O22 would be absorbed. would be absorbed. However, if 100 ml of blood is exposed to the same However, if 100 ml of blood is exposed to the same atmos, about 19 ml of Oatmos, about 19 ml of O22 would be absorbed. WHY? would be absorbed. WHY?

The total quantity of OThe total quantity of O22 bound with Hb in normal bound with Hb in normal systemic arterial blood is about 19.4 ml /100 ml of systemic arterial blood is about 19.4 ml /100 ml of blood. On passing through the tissue capillaries, this blood. On passing through the tissue capillaries, this amount is reduced to approx 14.4 ml. Therefore, 5 ml is amount is reduced to approx 14.4 ml. Therefore, 5 ml is the quantity of O2 that are transported from the lungs the quantity of O2 that are transported from the lungs to the tissues by each 100 ml of BF.to the tissues by each 100 ml of BF.

During heavy exercise, there might be upto 20 times During heavy exercise, there might be upto 20 times ↑ ↑ in Oin O22 transport to the tissues compared to normal. transport to the tissues compared to normal.

The OThe O22 carrying capacity carrying capacity is the vol of O2 contained in a vol of is the vol of O2 contained in a vol of O2 sat blood; the CC depends on the conc of effective Hb.O2 sat blood; the CC depends on the conc of effective Hb.

The CC is reduced in various forms of anemia (The CC is reduced in various forms of anemia (↓ No of RBC, ↓ No of RBC, insufficient prod of Hb or abnormal prod of Hb).insufficient prod of Hb or abnormal prod of Hb).

Failure of Hb prod occurs in dietary Failure of Hb prod occurs in dietary iron deficiency anemiairon deficiency anemia, because iron , because iron is needed for synthesis of haem group. Dietary deficiency or failure of is needed for synthesis of haem group. Dietary deficiency or failure of absorption of vit B12 causes absorption of vit B12 causes pernicious anemiapernicious anemia, in which formation of , in which formation of RBCs is impaired. In RBCs is impaired. In sickle cell anemiasickle cell anemia, substitution of a single AA in the , substitution of a single AA in the ββ chain causes Hb to aggregate into large polymers when PCOchain causes Hb to aggregate into large polymers when PCO22 is low. is low. People with various forms of People with various forms of thalassemiathalassemia, an inherited defect in the DNA, , an inherited defect in the DNA, have higher hematocrit levels than normal, but the RBCs contain less Hb, have higher hematocrit levels than normal, but the RBCs contain less Hb, and the Oand the O22 binding characteristics of Hb are abnormal. binding characteristics of Hb are abnormal.

Because almost all OBecause almost all O22 in the blood is carried and transported by in the blood is carried and transported by Hb, the relationship between the conc (pp) of OHb, the relationship between the conc (pp) of O22 and Hb sat (the % and Hb sat (the % Hb mol carrying OHb mol carrying O22 is very important. i.e. O is very important. i.e. O22-Hb dissociation curve.-Hb dissociation curve.

POPO22 is a very important factor to determine the extent of O is a very important factor to determine the extent of O22 binding to Hb. The relationship is shown by the curve.binding to Hb. The relationship is shown by the curve.

Factors which affect the OFactors which affect the O22-Hb dissociation curve:-Hb dissociation curve:These factors may shift the curve to the right, These factors may shift the curve to the right, indicating lower affinity of Hb to Oindicating lower affinity of Hb to O22, or shift the curve to , or shift the curve to the left, indicating an increased affinity of Hb to Othe left, indicating an increased affinity of Hb to O22. . These factors includes;These factors includes;

1) PCO1) PCO22::↑ PCO↑ PCO22 → ↓ affinity → ↓ affinity of Hb to Oof Hb to O22 → → shift the curve shift the curve to the right (this is called Bohr effect).to the right (this is called Bohr effect).

2) PH: 2) PH: ↓ PH (or ↑ [H↓ PH (or ↑ [H++]) → ↓ affinity ]) → ↓ affinity of Hb to Oof Hb to O22 → → shift the shift the curve to the right.curve to the right.3) Temp : 3) Temp : ↑↑ Temp Temp → → shift the curve to the right.shift the curve to the right.4) 2,3- diphosphoglycerate (2,3-DPG): :4) 2,3- diphosphoglycerate (2,3-DPG): :↑ ↑ 2,3-DPG2,3-DPG → ↓ → ↓ affinity affinity of Hb to Oof Hb to O22 → → shift the curve to the right. shift the curve to the right.

P50 is the pp of OP50 is the pp of O22 required to achieve 50% Hb sat. required to achieve 50% Hb sat.

Dissociation curve of myoglobinDissociation curve of myoglobinMyo is a heme-containing protein found in energetic tissues Myo is a heme-containing protein found in energetic tissues such as cardiac & skeletal muscle.such as cardiac & skeletal muscle.

Myo differs from Hb in that it consist of a single chain and can Myo differs from Hb in that it consist of a single chain and can bind only a single Obind only a single O22 mol. So it resembles Hb but binds one mol. So it resembles Hb but binds one rather than 4 mol of Orather than 4 mol of O22 per mole. However, Myo binds to O2 per mole. However, Myo binds to O2 more strongly than Hb.more strongly than Hb.

Myo dissociation curve is a rectangular hyperbola rather than Myo dissociation curve is a rectangular hyperbola rather than a sigmoid curve.a sigmoid curve.

Because its curve is to the left of Hb curve, it takes up OBecause its curve is to the left of Hb curve, it takes up O22 from from Hb in the blood.Hb in the blood.

Myo has 2 roles;Myo has 2 roles;1) it represents an intracellular reserve of O1) it represents an intracellular reserve of O22,,2) when the PO2) when the PO22 in the muscle cell has fallen very low, the in the muscle cell has fallen very low, the presence of Myo presence of Myo ↑ the rate of O↑ the rate of O22 diffusion from the cell surface to diffusion from the cell surface to interior.interior.

Hb in the fetusHb in the fetusThe blood of the human fetus normally contains fetal Hb (HbF). Its The blood of the human fetus normally contains fetal Hb (HbF). Its structure is similar to that of HbA except that the beta chains are structure is similar to that of HbA except that the beta chains are replaced by gamma chains. The gamma chains also contain 146 replaced by gamma chains. The gamma chains also contain 146 AA residues but have 37 that differ from those in the beta chain.AA residues but have 37 that differ from those in the beta chain.

HbF is normally replaced by HbA soon after birth.HbF is normally replaced by HbA soon after birth.

In the body, its OIn the body, its O22 content at a given PO content at a given PO22 is greater than that of is greater than that of HbA because it binds 2,3-DPG less avidly.HbA because it binds 2,3-DPG less avidly.

HbF is adapted to function at lower pp than those that will be HbF is adapted to function at lower pp than those that will be typical after birth.typical after birth.

Fetal-placental BF is affected by 2 hormone system best known in Fetal-placental BF is affected by 2 hormone system best known in adults for their role in ECF volume regulation; ADH system & renin-adults for their role in ECF volume regulation; ADH system & renin-angiotensin system.angiotensin system.

A ↓ in POA ↓ in PO22 of fetal arterial blood stimulates the release of ADH, whereas ↑ in of fetal arterial blood stimulates the release of ADH, whereas ↑ in POPO22 or a ↓ in PH stimulates the release of renin and ↑ in angiotensin II. or a ↓ in PH stimulates the release of renin and ↑ in angiotensin II.

COCO22 transport transport

COCO22 transported from the body cells back to the transported from the body cells back to the lungs in 3 forms;lungs in 3 forms;(1) Dissolved in the plasma (approx 7-10%).(1) Dissolved in the plasma (approx 7-10%).

(2) Reacts with the amino group of plasma (2) Reacts with the amino group of plasma proteins to form carbamino proteins proteins to form carbamino proteins (carbaminohemoglobin) (approx 23-30%).(carbaminohemoglobin) (approx 23-30%).

(3) Reacts with H2O to form H2CO3 (approx 60-(3) Reacts with H2O to form H2CO3 (approx 60-70%)70%)

COCO22 + H + H22O ↔ HO ↔ H22COCO33 ↔ HCO ↔ HCO33-- + H + H++

COCO22 dissociation curve dissociation curve

The volume of COThe volume of CO22 carried in the blood is determined by carried in the blood is determined by PCOPCO22. The dissolved form is directly proportionate to PCO. The dissolved form is directly proportionate to PCO22 (0.06 ml dissolved in 100 ml of blood/1 mmHg PCO(0.06 ml dissolved in 100 ml of blood/1 mmHg PCO22).).

The relationship of COThe relationship of CO22 content of blood to PCO content of blood to PCO22 is known as is known as COCO22 dissociation curve. dissociation curve.

The curve is affected by the saturation of Hb with OThe curve is affected by the saturation of Hb with O22 (Haldane effect).(Haldane effect).

Oxyhemoglobin shifts the curve to the right, i.e. in the lungs Oxyhemoglobin shifts the curve to the right, i.e. in the lungs COCO22 is released from the blood. is released from the blood.

Reduced Hb shifts the curve to the left, i.e. more COReduced Hb shifts the curve to the left, i.e. more CO22 is is taken up by the blood in the tissues. Thus , PCOtaken up by the blood in the tissues. Thus , PCO22 influences influences OO22 sat of Hb (Bohr effect) and PO sat of Hb (Bohr effect) and PO22 influences the CO influences the CO22 dissociation curve (Haldane effect). However, the Bohr effect dissociation curve (Haldane effect). However, the Bohr effect is much more potent and more important than the Haldane is much more potent and more important than the Haldane effect.effect.

Directional movement of CODirectional movement of CO22

All movement across membrane is by diffusion. All movement across membrane is by diffusion. Note that most of CONote that most of CO22 entering the blood in the entering the blood in the tissues ultimately is converted to HCOtissues ultimately is converted to HCO33

--. This . This occurs almost entirely in the erythrocytes occurs almost entirely in the erythrocytes because the CA enzyme is located there, but because the CA enzyme is located there, but most of the HCOmost of the HCO33

-- then moves out of the then moves out of the erythrocyte into the plasma in exchange for erythrocyte into the plasma in exchange for chloride ions “ the chloride shift”. chloride ions “ the chloride shift”.

Chloride shiftChloride shift

The rise in the HCOThe rise in the HCO33-- content of red cell is much greater content of red cell is much greater

than that in plasma as the blood passes through the than that in plasma as the blood passes through the capillaries. The excess of HCOcapillaries. The excess of HCO33

-- leaves the red cell in leaves the red cell in exchange for clexchange for cl--. This change is called the chloride shift.. This change is called the chloride shift.

The chloride shift occurs rapidly and essentially The chloride shift occurs rapidly and essentially complete in 1 second.complete in 1 second.

The clThe cl-- content of the red cells in venous blood is content of the red cells in venous blood is therefore significantly greater than in arterial blood.therefore significantly greater than in arterial blood.

In pulmonary capillaries; clIn pulmonary capillaries; cl-- leaves the red cell and leaves the red cell and move into the plasma in exchange for HCOmove into the plasma in exchange for HCO33

--; in ; in systemic capillaries, the reverse occurs.systemic capillaries, the reverse occurs.

The Haldane effectThe Haldane effect

It results from the simple fact that the combination It results from the simple fact that the combination of Oof O22 with Hb in the lung causes the Hb to become with Hb in the lung causes the Hb to become a stronger acid.This displaces COa stronger acid.This displaces CO22 from the blood from the blood and into the alveoli in 2 ways;and into the alveoli in 2 ways;(1) The more highly acidic Hb has less tendency to (1) The more highly acidic Hb has less tendency to combine with COcombine with CO22 to form carbaminohemoglobin, to form carbaminohemoglobin, thus displacing much of the COthus displacing much of the CO22 that is present in that is present in the carbamino form from the blood.the carbamino form from the blood.(2) The ↑ acidity of Hb also causes it to release an (2) The ↑ acidity of Hb also causes it to release an excess of Hexcess of H++, and these bind with HCO, and these bind with HCO33

-- to form to form HH22COCO33; this then dissociate into H; this then dissociate into H22O and COO and CO22, and , and the COthe CO22 is released from the blood into the alveoli is released from the blood into the alveoli and, finally, into the air.and, finally, into the air.