10. Carriage of O2 in the blood Flashcards
What is the purpose of the cardiovascular system?
Supply oxygen and metabolic fuel e.g. glucose to tissues and to take away the waste product of metabolism i.e. CO2
To maintain defences against invading microorganisms
Why is the simple carriage of oxygen a problem?
How do we overcome this?
Because O2 is a powerful oxidising agent
Most organic molecules are damaged by too high a concentration of O2
Erythrocytes are specific for this task
Define and describe ‘oxidation’
The loss of electrons
Oxidising agents e.g. molecular O2 are ‘electron hungry’ so when they combine with other atoms or electrons they remove the electrons from the oxidised molecule
Oxidation simplifies the electronic structure of the substrate and hence, decreases the free energy of the system
This releases energy - most often in the form of heat
Define and describe ‘reduction’
The gain/adding of electrons
Involves the building of molecules from simpler ones
Normally requires energy
Describe O2 as an oxidising agent
Powerful oxidising agent
One O2 molecules takes 4 electrons from an organic substrate
Describe erythrocytes
Describe the breakdown of erythrocytes and how this occurs
Contains Hb - contains about 270 million Hb molecules
Bioconcave disks
Volume of about 80 cubic microns
Have no nuclei - SO they cannot synthesise any RNA and hence, cannot divide or repair themselves and so have a limited lifetime of about 120 days
Have no mitochondria - SO cannot use any of the O2 that they carry
Ageing RBC undergoes changes in it’s plasma membrane which makes it susceptible to recognition by phagocytes and subsequent phagocytosis in the spleen, liver and bone marrow
Describe why RBCs require ATP and how they form this
Require ATP to maintain sodium pumps in their cell membranes and for ion pumping operations
Produce ATP by glycolysis - glucose to pyruvate and pyruvate to lactic acid
SO they have a naturally low pH
RBCs have a separate uptake of glucose system to other cells in the body - not regulated by insulin
Describe Hb and why it is unique
Explain why Hb is able to do this
Unique because it can combine rapidly and reversibly with O2 without becoming oxidised
SO it can release the O2 to tissues when required
This is due to the presence of the iron atom and its special properties - ferrous iron atom has 6 unpaired electrons and hence, can form bonds with 6 electrons from other atoms
Describe the effect that oxygen has on RBCs
RBCs are progressively damaged by the O2 they carry
Hb is converted to methaemaglobin (oxidised Hb)
Other enzymes become oxidised and inactive
Cells are also damaged by having to bend to get through the smallest capillaries
What are reticulocytes? Describe these
Just before and after leaving the bone marrow, immature erythrocytes are known as reticulocytes
These comprise about 1-2% of the circulating erythrocytes in a normal person - they change into erythrocytes about a day after entering the circulation
They have this name due to the reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains e.g. methylene blue
Describe the ferrous iron that is present in Hb
Has 6 unpaired electrons - can form bonds with 6 electrons from other atoms
4 bonding orbitals are in a plane and 2 stick out above and below the plane
The 4 in the same plane are held tight by 4 covalent bonds to nitrogen atoms in a porphyrin ring
5th electron is bonded to histidine amino acid under the plane
This leaves a single 6th ferrous electron able to form a bond
In Hb O2 forms a weak reversible bond with the 6th ferrous electron
Describe the structure of human Hb
Made up of four polypeptide subunits
Each subunit has a haem prosthetic group attached
The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds and hydrophobic interactions
Describe what is meant by ‘steric hindrance’ and how this relates to Hb
Steric hindrance is the stopping of a chemical reaction due to the structure of the molecules
The 3D folding of the Hb subunits creates a steric hindrance so O2 cannot get close enough to iron to remove it’s electrons
In Hb, O2 meets iron in the Fe++ state and does not remove the 6th electron completely
This means that it does not leave iron in the Fe+++ form (ferric state)
This is due to the steric hindrance
What is the impact of steric hindrance in Hb?
Steric hindrance in Hb results in the formation of a resonance structure where O2 is weakly bonded to iron but does not oxidise it
This is dependent on the pO2 in solution e.g. when the pO2 is high (lungs) the O2 can bind and form this oxyhaemoglobin resonance structure
If the steric hindrance is not correct then O2 does oxidise the iron to it’s ferric state - Hb with ferric iron is called methaemoglobin and cannot carry O2
Describe methaemoglobin and it’s significance
The formation of methaemoglobin is another reason with RBCs have a limited lifespan - once this forms in aged cells, the cells become full of it and need to be replaced
A small amount of methaemoglobin is formed whenever the RBCs pass through the lungs
In young cells, most of this can be converted back to Hb by the NADH dependent enzyme methaemoglobin reductase inside the cell but in ageing cells, the amount of methaemaglobin increases (possibly because NADH levels decrease)
One signal that an erythrocyte should be removed from circulation is an increased concentration of methaemoglobin in the cell - causes antigen markers on the surface of the cell to change and this change is detected by cells in the liver and the spleen, which remove the exhausted erythrocytes
About 1-2% of people’s Hb is methaemoglobin - a higher percentage of this can be due to genetic causes or due to exposure to various chemicals - known as mehaemoglobinemia
Describe the different subunits of Hb
Several forms of Hb subunit globin e.g. alpha, beta
Each form has a slightly different amino acid sequence
All subunits contain the haem group but the amount of steric hindrance varies depending on the particular mix of subunits in the molecule
Folding of the subunits and the ability of O2 to bind to them is altered by other factors such as pH and CO2
Describe the subunits present in adult Hb
Normally made up of two alpha subunits and two beta subunits - HbA
Describe the subunits present in foetal Hb
Two gamma subunits
This has a higher affinity for O2 than adult Hb and can hence remove it from the placental blood
Describe the effect of mutations in Hb and two common diseases this results in
Mutations in the genes for Hb protein in humans can result in a group of hereditary diseases
These are termed the haemoglobinopathies
Most common are sickle cell anaemia and thalassaemia
Briefly describe the Hb changes in SCA
When foetal Hb is switched off after birth, instead of producing normal HbA, HbS is produced
HbS contains mutant form of one of the beta subunits
This is because a valine replaces a glutamine in the 6th position of the beta chain of globin
Briefly describe the Hb changes in thalassaemia
Inherited autosomal recessive blood disease
Genetic defect - could be either mutation or deletion which results in a reduced rate of synthesis of one of the globin chains that make up Hb
Reduced rate results in abnormal Hb which causes the disease
What is the oxygen/Hb dissociation curve?
This is the curve that relates the oxygen binding to Hb to the partial pressure of O2
Explain the shape of the curve
The progressive binding of O2 to the four subunits of Hb is the reason for the characteristic shape of this curve
The curve is S shaped
Flat curve at a high pO2
This means that Hb is more than 90% saturated by O2 over a wide range of pO2 in the lungs
This ranges from pO2 of 70mmHg to >100mmHg
Steep curve at medium and low pO2
This means that Hb releases large amounts of O2 for a small decrease in pO2 over the range of 20-40mmHg (remember that the purpose of Hb is to release the O2)
What factors affect the oxygen/Hb curve?
Heat
PH
Describe the impact of heat/lack of heat on oxygen/Hb curve
Heavily metabolising tissue heats up
Heat moves the Hb curve to the right and so unloads more O2 at any given partial pressure
Slowly metabolising tissue is colder than normal
Cold moves the Hb curve sharply to the left
A cold limb may become hypoxic and feel fatigued even if well perfused
Describe the impact of heat on the oxygen/Hb curve and what this is called
Heavily metabolising tissue generates more CO2 and so the tissue becomes more acidic
Lower pH moves the curve to the right
This pH driven shift is called the Bohr shift
What is myoglobin? Describe it’s role in the body
This is a form of Hb found in muscle
It is a single subunit
Mb has a greater affinity for O2 than Hb - SO O2 is transferred to MbO2 as blood passes through muscle capillaries
Hence, Mb forms a ‘buffer store’ of O2 in muscle
NB. When myoglobin is released from damaged muscle tissue, this process is called rhabdomyolysis and the released Mb is filtered by the kidneys – it is toxic to the renal tubular epithelium so may cause acute renal failure
Why is carbon monoxide toxic?
It has a greater affinity for Hb than O2
Blood leaving the lungs will hence contain mostly carboxyhaemoglobin and the person will die from hypoxia
What is haematocrit?
This is the percentage of blood that is red blood cells – normally about 45%
The amount of O2 that is carried is dependent on the haematocrit
How is the haematocrit level regulated?
Haematocrit is controlled by a hormone erythropoietin (EPO)
EPO is continually released from the kidney and the liver
It stimulates the production of red blood cells in the bone marrow
When the kidney is hypoxic, EPO secretion is increased SO negative feedback loop
EPO is also used as a therapeutic agent to treat anaemia resulting from chronic kidney disease, chemotherapy and radiation and other critical diseases such as heart failure
Explain how CO2 is transported in the blood
Red blood cells also carry CO2 back to the lungs
Although CO2 is very water soluble, this solubility is not enough to carry all the CO2 generated by the body back to the lungs
The RBCs convert the CO2 to bicarbonate via the enzyme carbonic anhydrase
Most of the bicarbonate that is formed is expelled into the plasma and carried in the venous blood to the lungs
As the bicarbonate diffuses out, Cl- ions diffuse into the RBC to maintain electrical neutrality
In the lungs, the bicarbonate re-enters the RBC and is converted back to CO2 and then released into the alveoli
Cl- leaves the RBC to balance the electrical charge of the HCO3- entering the cell
CO2 can also be carried to the lungs as carbaminohaemoglobin – CO2 binds to oxyhaemoglobin and displaces O2 in acid conditions
In the lungs, the high partial pressure of O2 and low pH displaces the CO2 and haemoglobin and oxyhaemoglobin is reformed
OVERALL most CO2 is carried back to the lungs in the form of bicarbonate, not as a dissolved gas
