I. Circulatory system functions:

A. gas exchange: oxygen, carbon dioxide, ammonia

B. nutrients to the cells

C. communication between cells via hormones.

D. heat distribution

E. waste removal: carbon dioxide, nitrogen wastes, others

F. protective systems:

1. immune system of antibodies.

2. phagocytitic cells to remove small foreign particles.

3. self repair mechanism via clotting

G. regulation systems:

1. osmotic balance in cells.

2. pH and other ions.

H. development of mechanical force.

II. Blood carrying capacity of oxygen.

A. The water aspect of blood can carry a certain amount of oxygen, for which Henry's law would apply.

(Typical oxygen tension in lungs is about 100 mm Hg; typical oxygen tension at tissues is about 30 mm Hg => shaded area)

B. It would be a good mechanism to have something else in the blood that could bind O2 at the lungs and deposit it in the tissues. One might ideally achieve this with a curve such as:

C. Unfortunately the kinetics of reversible binding molecules do not behave this way. The laws of chemistry in fact indicate quite a different curve for the simplest reversible binding reaction:

(Myoglobin in fact behaves like this)

D. Hemoglobin comes close to "fooling" those chemical laws and approaches the curve seen in B.

E. Hemoglobin achieves this by a) being made up of 4 subunits thus binding four molecules of O 2 and b) the shape of the hemoglobin changes after each molecule of O2 is bound such that it is easier to bind the next molecule of O 2. Thus, the first molecule of O 2 is hard to put on, but each of the next ones is easier as seen in the saturation curve:

1. Hemoglobin structure: 4 hemes, 4 globins.

a. A heme has an iron atom and is built into a organic ring (porphyrin ring) which includes 4 nitrogens.

2. The globin is the protein part of the molecule and can be very different form animal to animal.

3. Oxyhemoglobin

F. There are many different kinds of respiratory pigments and different kinds of hemoglobins.

1. Iron is the most common metallic element in respiratory pigments; but copper is also frequently found.

2. Respiratory pigments, including hemoglobins, have apparently independently evolved several times.

a. These pigments undoubtedly have evolved from the cytochromes of the respiratory chain which have Fe and Cu porphyrin rings.

b. There is a wide variety of formats in which hemoglobin and other respiratory pigments are found.

c. Unique respiratory pigments seem to 'suddenly' appear in certain animal groups and even in certain plants and bacteria!

III. Hemoglobin is an amazing molecule:

Hemoglobin curves can be changed on the basis of genetics(different primary structure), pH, temp, chemicals(DPG, CO2, )

B. Bohr effect - here a single molecule is very effective in achieving a major aspect of control of respiration, unlike the complex nervous interactions that had been discussed before:

High CO 2, which which will lead to low pH i n hard working cells, will stimulate the release of O2 from hemoglobin. The higher acidity will stimulate higher ventilation, but it will also change the nature of hemoglobin molecule (Bohr effect) in such a way that it more readily releases the O2 to the tissues. When the tissues return to normal levels of CO 2, the hemoglobin returns to its normal binding capacity.

C. Smaller homeotherms, on a per cell basis, uses more O2 and creates more CO2 at the tissue than do larger animals. Thus, a stronger Bohr effect is advantageous to smaller animals. Hemoglobin with a lower O2 affinity facilitates the release of O2 into tissue.

D. Fetal hemoglobin has a higher affinity for O2 so that the fetus can successfully compete for O2 from the parental mother (commonly found in mammals). The fetal hemoglobin is genetically different and the mother's hemoglobin has ¨nusually high levels of DPG.

E. High altitude corresponding to low O2 level.

1. Llama, a high altitude ungulate, has a genetically different hemoglobin with higher O 2 affinity facilitating the uptake of O 2 into the lungs.

2. Man increases (after about 24 hours at high altitude) the diphosphoglycerate (DPG) level which decreases the O2 affinity facilitating the release of O2 to the tissues. (ATP does the same thing)

F. Hemoglobin facilitates the diffusion of oxygen (somehow). This may allow certain cells to be farther away from a circulating oxygen source than normally may be possible.

G. Hemoglobin is often stored in cells within the circulatory systems and would be called red blood cells (=erythrocyte).

a. Red blood cells of mammals have lost all of their organelles including the nucleus.

b. The advantage of packaging hemoglobin into cells seems to be in helping control the environment of the hemoglobin, and thus controlling the oxygen binding characteristics. Packaging of hemoglobin does not reduce viscosity, as once thought.

c. Human blood is made up of about 45% red blood cells. Each cell is about 35 % hemoglobin.

H. Hemoglobin has the ability to also carry a significant amount of carbon dioxide. It does so at a different binding site than that for oxygen. Although an oxygenated hemoglobin molecule can simultaneously carry a CO2 molecule, there is a slight lessened tendency to do so.

I. When 'worn out' hemoglobin is broken down, the iron is removed from the porphyrin ring, and the remaining porphyrin ring is called bilirubin which is a waste which must be removed.

IV. To ask the question if one hemoglobin dissociation curve is better than another you must ask the following questions:

1. What is the alveolar oxygen tension?

2. What is the tissue oxygen tension?

3. What is the amount of oxygen released in going from the alveolar oxygen tension to the tissue oxygen tension for the particular hemoglobin dissociation curve in question?

4. How much oxygen should be kept in reserve for unusual and extreme situations to maximize the survival of the animal?

V. How does carbon dioxide get moved from the cells?:

A. There are three ways CO2 can be carried in blood:

1. CO 2 is much more soluble in water (the major component of blood) than is oxygen.

2. CO 2 can reversibly bind to hemoglobin.

3. CO 2 can react with water to form carbonic acid thus greatly increasing the capacity of water to hold carbon dioxide.

a. Carbonic acid is a major buffer in blood. A typical blood pH is around 7.4.

b. At pH 7.4, carbonic acid mostly exists as HCO3- .

c. CO2 in the blood, because of its role in pH, is important in its own right. For example, too little CO 2 could be a problem. In one sense CO 2 is a waste, in another sense it is not.

d. Blood is strongly buffered. Other buffers include the proteins and phosphates.

e. Since the reaction of CO2 with water is a reaction, the reversibility is limited.

B. The dissociation curve for CO2 is a classic binding curve as shown in IIC. above.

C. Although the smallest amount of CO2 is dissolved directly in the water, it is probably where most CO 2 exchange occurs because it is the most readily available. Exchange of CO2 on and off of hemoglobin is probably significantly important. The actual reaction with water to form carbonic acid is probably minimal in the bulk of CO 2 that gets exchanged. Nevertheless this reaction is still very important because of the acid base balance and acidic effects (such as the Bohr effect).

a. Carbonic anhydrase catalyzes the reversible reaction of CO 2 with H2 O. Inhibition of this enzyme suggests that it has no major effect on the direct exchange of CO2, but it does probably affect pH balance, Bohr effect, buffering, etc.

II. Components of blood:

A. Hematocrit shows there is about 45% RBCs.

B. ERYTHROCYTE = RED BLOOD CELL = RBC

1. biconcave disk about 8 micrometers in diameter. No nucleus.

2. 120 day lifetime. 5 million per milliliter.

3. Red blood cells are formed (erythropoiesis) only in red bone marrow in adults.

a. hemocytoblasts are the stem cells from which all blood cells arise.

b. In making erythrocytes, the hemocytoblasts divide into structures destined to become red blood cells.

c. Initially there is no hemoglobin in the cells and they have their full complement of organelles.

d. Several mitotic divisions occur and the cells start to produce hemoglobin and lose some of their organelles. The nucleus is eventually lost by extrusion and the cell is ready to enter the blood stream.

e. The red blood cell that enters the blood stream is called a reticulocyte . It is somewhat larger than a RBC and still has much of its endoplasmic reticulum which can be stained. Within a day or two they lose these organelles and become full fledged erythrocytes. A high concentration of reticulocytes indicates a high production rate of red blood cells.

4. "bag of" hemoglobin - a protein making up about 33% of the cell volume.

a. The hemoglobin molecule is made up of four heme groups (each containing one iron atom) and one globin molecule (a protein).

b. Each heme group specifically binds one oxygen molecule.

c. Hemoglobin also nonspecifically binds carbon dioxide.

d. Hemoglobin gives blood its distinctive red color.

e. When red blood cells are destroyed the heme and iron is not recycled, but rather is transformed into the molecule bilirubin which is mostly taken up by the liver and excreted in the feces via bile. Some bilirubin also leaves via the urine. The iron gives feces and urine their distinctive color.

5. Different people have different erythrocytes with different surface proteins. A person will (if given the chance) form antibodies against proteins that are not their own. For example the 'universal' blood donor (type - O) has essential no surface proteins and thus would affect no one else. On the other hand, the universal recipient (type AB) has both of the critical the surface proteins (A and B) and therefore would not make antibodies against either of these. Rh is another group of surface proteins.

6. Anemia means that the number of red blood cells or the hemoglobin concentration is too low.

C. Platelets = thrombocytes. cell fragments? Extremely small. Involved in blood clotting

D. LEUCOCYTES = WHITE BLOOD CELLS = WBC

1. 7000/ml they live only a few days much larger than an RBC. Have full complement of organelles. Often resemble amoebae. Many can leave the circulatory system and move through the tissues!

2. GRANULOCYTES develop from red bone marrow. Have large cytoplasmic granules. Names are based upon their staining characteristics.

a. neutrophils Multilobed nucleus. Helps kill invading bacteria by phagocytosis and release of lysozyme.

b. eosinophils-destroy antibody-antigen complexes. Also destroys histamine.

c. basophils Release localized hormones such as histamine; involved in allergies.

3. AGRANULOCYTES develop mostly from lymph tissue.

a. lymphocytes Quite small (~9µm). Important in antibody formation. Originate in bone marrow but can migrate to lymph nodes and continue to reproduce! (apparently there are many different kinds of lymphocytes to produce the variety of different hormones)

b. monocytes. Very large. phagocytitic - long term)

4. DIFFERENTIAL COUNT: proportion of the types of white blood cells. Extremely useful in disease detection.

5. ANTIBODY formation. Antibodies are proteins made by white blood cells that work against antigens (foreign molecules that enter the body).

D. Plasma - the blood with all formed elements removed.

1. Water

2. Clotting proteins and factors. When plasma has the clotting proteins removed, the remaining fluid is called serum.

3. Proteins:

a. albumin - blood viscosity, osmotic balance, buffer.

b. globulins antibodies and transport molecules.

c. fibrinogen-blood clotting protein.

d. complement-part of immune system

4. Ions. - Na+, K+, Ca ++, Mg++, HCO3- ,HPO4--, Cl-, Fe++ , H+, ...

5. Nutrients: (Glucose, Amino acids, vitamins, cholesterol, fatty acids).

6. Gases: (CO2, O2, N2).

7. Wastes:

a. nitrogen wastes from protein breakdown (ammonia, urea, uric acid)

b. bilirubin - an iron waste from dead red blood cells.

8. Enzymes

9. Hormones.

E. Blood clotting.

1. Many steps and chemicals involved.

2. Platelet plugs.

3. Clot formation in simplified terms: