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Physiology - NEETMDS- courses
NEET MDS Lessons
Physiology

Oxygen Transport in Blood: Hemoglobin

A.    Association & Dissociation of Oxygen + Hemoglobin

1.    oxyhemoglobin (HbO2) - oxygen molecule bound
2.    deoxyhemoglobin (HHb) - oxygen unbound
    
H-Hb     +    O2  <= === => HbO2 + H+

3.    binding gets more efficient as each O2 binds
4.    release gets easier as each O2 is released

5.    Several factors regulate AFFINITY of O2

a.    Partial Pressure of O2
b.    temperature
c.    blood pH (acidity)
d.    concentration of “diphosphoglycerate” (DPG)

B.    Effects of Partial Pressure of O2

1.  oxygen-hemoglobin dissociation curve

a.    104 mm (lungs) - 100% saturation (20 ml/100 ml)
b.    40 mm (tissues) - 75% saturation (15 ml/100 ml)
c.    right shift - Decreased Affinity, more O2 unloaded
d.     left shift- Increased Affinity, less O2 unloaded


C.    Effects of Temperature
    
1.    HIGHER Temperature    --> Decreased Affinity (right)
2.    LOWER Temperature        --> Increased Affinity (left)

D.    Effects of pH (Acidity) 

1.    HIGHER pH    --> Increased Affinity (left)
2.    LOWER pH    --> Decreased Affinity (right) "Bohr Effect"
a.    more Carbon Dioxide, lower pH (more H+), more O2 release

E.    Effects of Diphosphoglycerate (DPG)

1.    DPG - produced by anaerobic processes in RBCs
2.    HIGHER DPG    > Decreased Affinity (right)
3.    thyroxine, testosterone, epinephrine, NE - increase RBC metabolism and DPG production, cause RIGHT shift

F.    Oxygen Transport Problems

1.    hypoxia - below normal delivery of Oxygen

a.    anemic hypoxia - low RBC or hemoglobin
b.    stagnant hypoxia - impaired/blocked blood flow
c.    hypoxemic hypoxia - poor lung gas exchange

2.    carbon monoxide poisoning - CO has greater Affinity than Oxygen or Carbon Dioxide 
 

Remember the following principles before proceeding :
- Reabsorption occurs for most of substances that have been previously filterd .
- The direction of reabsorption is from the tubules to the peritubular capillaries
- All of transport mechanism are used here.
- Different morphology of the cells of different parts of the tubules contribute to reabsorption of different substances .
- There are two routes of reabsorption: Paracellular and transcellular : Paracellular reabsorption depends on the tightness of the tight junction which varies from regeon to region in the nephrons .Transcellular depends on presence of transporters ( carriers and channels for example).


1. Reabsorption of glucose , amino acids , and proteins :

Transport of glucose occurs in the proximal tubule . Cells of proximal tubules are similar to those of the intestinal mucosa as the apical membrane has brush border form to increase the surface area for reabsorption , the cells have plenty of mitochondria which inform us that high amount of energy is required for active transport , and the basolateral membrane of the cells contain sodium -potassium pumps , while the apical membrane contains a lot of carrier and channels .

The tight junction between the tubular cells of the proximal tubules are not that (tight) which allow paracellular transport.
Reabsorption of glucose starts by active transport of  Na by the pumps on the basolateral membrane . This will create Na gradient which will cause Na to pass the apical membrane down its concentration gradient . Glucose also passes the membrane up its concentration gradient using sodium -glucose symporter as a secondary active transport.


The concentration of glucose will be increased in the cell and this will enable the glucose to pass down concentration gradient to the interstitium by glucose uniporter . Glucose will then pass to the peritubular capillaries by simple bulk flow.

Remember: Glucose reabsorption occurs via transcellular route .
          Glucose transport has transport maximum . In normal situation there is no glucose in the urine , but in uncontrolled diabetes mellitus patients glucose level exceeds its transport maximum (390 mg/dl) and thus will appear in urine .
                   
                   
                   
2. Reabsorption of Amino acids : Use secondary active transport mechanism like glucose.

3. Reabsorption of proteins : 

Plasma proteins are not filtered in Bowman capsule but some proteins and peptides in blood may pass the filtration membrane and then reabsorbed . Some peptides are reabsorbed paracellulary , while the others bind to the apical membrane and then enter the cells by endocytosis , where they will degraded by peptidase enzymes to amino acids .

4. Reabsorption of sodium , water , and chloride:

65 % of sodium is reabsorbed in the proximal tubules , while 25% are reabsorbed in the thick ascending limb of loob of Henle , 9% in the distal and collecting tubules and collecting ducts .
90% of sodium reabsorption occurs independently from its plasma level (unregulated) , This is true for sodium reabsorbed in proximal tubule and loop of Henle , while the 9% that is reabsorbed in distal ,collecting tubules and collecting ducts is regulated by Aldosterone. 


In proximal tubules : 65% of sodium is reabsorbed . The initial step occurs by creating sodium gradient  by sodium-potassium pump on the basolateral membrane . then the sodium will pass from the lumen into the cells down concentration gradient by sodium -glucose symporter , sodium -phosphate symporter and by sodium- hydrogen antiporter and others                    
                   
After reabsorption of sodium , an electrical gradient will be created , then chloride is reabsorbed following the sodium  . Thus the major cation and anion leave the lumen to the the interstitium and thus the water follows by osmosis . 65% of water is reabsorbed in the proximal tubule.

Discending limb of loop of Henle is impermeable to electrolytes but avidly permeable to water . 10 % of water is reabsorbed in the discending thin limb of loob of Henle .

The thick ascending limb of loop of Henly is permeable to electrolytes , due to the presence of Na2ClK syporter . 25% of sodium is reabsorbed here .

In the distal and collecting tubules and the collecting ducts 9% of sodium is reabsorbed .this occurs under aldosterone control depending on sodium plasma level. 1% of sodium is excreted .

Water is not reabsorbed from distal tubule but 5-25% of water is reabsorbed in collecting tubules .

Oxygen Uptake in the Lungs is Increased About 70X by Hemoglobin in the Red Cells

  • In the lungs oxygen must enter the blood
  • A small amount of oxygen dissolves directly in the serum, but 98.5% of the oxygen is carried by hemoglobin
  • All of the hemoglobin is found within the red blood cells (RBCs or erythrocytes)
  • The hemoglobin content of the blood is about 15 gm/deciliter (deciliter = 100 mL)
  • Red cell count is about 5 million per microliter

Each Hemoglobin Can Bind Four O2 Molecules (100% Saturation)

  • Hemoglobin is a protein molecule with 4 protein sub-units (2 alphas and 2 betas)
    • Each of the 4 sub-units contains a heme group which gives the protein a red color
    • Each heme has an iron atom in the center which can bind an oxygen molecule (O2)
    • The 4 hemes in a hemoglobin can carry a maximum of 4 oxygen molecules
  • When hemoglobin is saturated with oxygen it has a bright red color; as it loses oxygen it becomes bluish (cyanosis)

The Normal Blood Hematocrit is Just Below 50%

  • Blood consists of cells suspended in serum
  • More than 99% of the cells in the blood are red blood cells designed to carry oxygen
    • 25% of all the cells in the body are RBCs
  • The volume percentage of cells in the blood is called the hematocrit
  • Normal hematocrits are about 40% for women and 45% for men

At Sea Level the Partial Pressure of O2 is High Enough to Give Nearly 100% Saturation of Hemoglobin

  • As the partial pressure of oxygen in the alveoli increases the hemoglobin in the red cells passing through the lungs rises until the hemoglobin is 100% saturated with oxygen
    • At 100% saturation each hemoglobin carries 4 O2 molecules
    • This is equal to 1.33 mL O2 per gram of hemoglobin
  • A person with 15 gm Hb/deciliter can carry:
    • Max O2 carriage = 1.33 mL O2/gm X 15 gm/deciliter = 20 mL O2/deciliter
  • A plot of % saturation vs pO2 gives an S-shaped "hemoglobin dissociation curve"
  • At 100% saturation each hemoglobin binds 4 oxygen molecules

At High Altitudes Hemoglobin Saturation May be Well Below 100%

  • At the alveolar pO2 of 105 mm Hg at sea level the hemoglobin will be about 97% saturated, but the saturation will fall at high altitudes
  • At 12,000 feet altitude alveolar pO2 will be about 60 mm Hg and the hemoglobin will be 90% saturated
  • At 29,000 feet (Mt. Everest) alveolar pO2 is about 24 mm Hg and the hemoglobin will be only 42% saturated
  • At very high altitudes most climbers must breath pure oxygen from tanks
  • During acclimatization to high altitude the hematocrit can rise to about 60%- this increases the amount of oxygen that can be carried
  • Hematocrits above 60% are not useful because the blood viscosity will increase to the point where it impairs circulation

Blood is a liquid tissue. Suspended in the watery plasma are seven types of cells and cell fragments.

  • red blood cells (RBCs) or erythrocytes
  • platelets or thrombocytes
  • five kinds of white blood cells (WBCs) or leukocytes
    • Three kinds of granulocytes
      • neutrophils
      • eosinophils
      • basophils
    • Two kinds of leukocytes without granules in their cytoplasm
      • lymphocytes
      • monocytes

Carbohydrates:

  • about 3% of the dry mass of a typical cell
  • composed of carbon, hydrogen, & oxygen atoms (e.g., glucose is C6H12O6)
  • an important source of energy for cells
  • types include:
    • monosaccharide (e.g., glucose) - most contain 5 or 6 carbon atoms
    • disaccharides
      • 2 monosaccharides linked together
      • Examples include sucrose (a common plant disaccharide is composed of the monosaccharides glucose and fructose) & lactose (or milk sugar; a disaccharide composed of glucose and the monosaccharide galactose)
    • polysaccharides
      • several monosaccharides linked together

Examples include starch (a common plant polysaccharide made up of many glucose molecules) and glycogen (commonly stored in the liver)

Red blood cell cycle:

RBCs enter the blood at a rate of about 2 million cells per second. The stimulus for erythropoiesis is the hormone erythropoietin, secreted mostly by the kidney. RBCs require Vitamin B12, folic acid, and iron. The lifespan of RBC averages 120 days. Aged and damaged red cells are disposed of in the spleen and liver by macrophages. The globin is digested and the amino acids released into the blood for protein manufacture; the heme is toxic and cannot be reused, so it is made into bilirubin and removed from the blood by the liver to be excreted in the bile. The red bile pigment bilirubin oxidizes into the green pigment biliverdin and together they give bile and feces their characteristic color. Iron is picked up by a globulin protein (apotransferrin) to be transported as transferrin and then stored, mostly in the liver, as hemosiderin or ferritin. Ferritin is short term iron storage in constant equilibrium with plasma iron carried by transferrin. Hemosiderin is long term iron storage, forming dense granules visible in liver and other cells which are difficult for the body to mobilize.

Some iron is lost from the blood due to hemorrhage, menstruation, etc. and must be replaced from the diet. On average men need to replace about 1 mg of iron per day, women need 2 mg. Apotransferrin (transferrin without the iron) is present in GI lining cells and is also released in the bile. It picks up iron from the GI tract and stimulates receptors on the lining cells which absorb it by pinocytosis. Once through the mucosal cell iron is carried in blood as transferrin to the liver and marrow. Iron leaves the transferrin molecule to bind to ferritin in these tissues. Most excess iron will not be absorbed due to saturation of ferritin, reduction of apotransferrin, and an inhibitory process in the lining tissue.

 

Erythropoietin Mechanism:

Myeloid (blood producing) tissue is found in the red bone marrow located in the spongy bone. As a person ages much of this marrow becomes fatty and ceases production. But it retains stem cells and can be called on to regenerate and produce blood cells later in an emergency. RBCs enter the blood at a rate of about 2 million cells per second. The stimulus for erythropoiesis is the hormone erythropoietin, secreted mostly by the kidney. This hormone triggers more of the pleuripotential stem cells (hemocytoblasts) to follow the pathway to red blood cells and to divide more rapidly.

 

It takes from 3 to 5 days for development of a reticulocyte from a hemocytoblast. Reticulocytes, immature rbc, move into the circulation and develop over a 1 to 2 day period into mature erythrocytes. About 1 to 2 % of rbc in the circulation are reticulocytes, and the exact percentage is a measure of the rate of erythropoiesis.

Maintenance of Homeostasis


The kidneys maintain the homeostasis of several important internal conditions by controlling the excretion of substances out of the body. 

Ions. The kidney can control the excretion of potassium, sodium, calcium, magnesium, phosphate, and chloride ions into urine. In cases where these ions reach a higher than normal concentration, the kidneys can increase their excretion out of the body to return them to a normal level. Conversely, the kidneys can conserve these ions when they are present in lower than normal levels by allowing the ions to be reabsorbed into the blood during filtration. (See more about ions.)
 
pH. The kidneys monitor and regulate the levels of hydrogen ions (H+) and bicarbonate ions in the blood to control blood pH. H+ ions are produced as a natural byproduct of the metabolism of dietary proteins and accumulate in the blood over time. The kidneys excrete excess H+ ions into urine for elimination from the body. The kidneys also conserve bicarbonate ions, which act as important pH buffers in the blood.
 
Osmolarity. The cells of the body need to grow in an isotonic environment in order to maintain their fluid and electrolyte balance. The kidneys maintain the body’s osmotic balance by controlling the amount of water that is filtered out of the blood and excreted into urine. When a person consumes a large amount of water, the kidneys reduce their reabsorption of water to allow the excess water to be excreted in urine. This results in the production of dilute, watery urine. In the case of the body being dehydrated, the kidneys reabsorb as much water as possible back into the blood to produce highly concentrated urine full of excreted ions and wastes. The changes in excretion of water are controlled by antidiuretic hormone (ADH). ADH is produced in the hypothalamus and released by the posterior pituitary gland to help the body retain water.
 
Blood Pressure. The kidneys monitor the body’s blood pressure to help maintain homeostasis. When blood pressure is elevated, the kidneys can help to reduce blood pressure by reducing the volume of blood in the body. The kidneys are able to reduce blood volume by reducing the reabsorption of water into the blood and producing watery, dilute urine. When blood pressure becomes too low, the kidneys can produce the enzyme renin to constrict blood vessels and produce concentrated urine, which allows more water to remain in the blood.

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