Human Physiology Part 3 - Respiratory, Urinary and Endocrine Systems
p1
TRANSPORT OF GASES
I. Gas transport C6H12O6 + 6O2 -> 6CO2 + H2O.
One of the functions of blood is taking Oxygen to the tissues and removing CO2 from the tissues.
A. Oxygen transport. The solubility of oxygen in water is .3 ml to 100ml plasma. On the other hand,
whole blood carries 20ml per 100ml. This difference is due to hemoglobin.
Volume % = ml gas/100ml fluid.
So Blood plasma carries .3 volume %. Whole blood carries 20 volume %.
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Oxygen transport is primarily via red blood cells, which have hemoglobin. Hemoglobin is made up of 2
different protein chains. Alpha and beta chains, which are very similar. The 4 chains together make up a
hemoglobin molecule. Within hemoglobin there is a crucial subunit called heme. This heme group with
a central ion associates with an Oxygen molecule. It is not a covalent bonding. There is a physical
attraction (charge). The ion can take on and give off an oxygen molecule very easily. We have one
oxygen that can associates with each ion. So a hemoglobin molecule can associate with 4 Oxygen
molecules.
In associating with oxygen, the individual units change in position with respect to each other. As O2
comes in the actual hemoglobin molecule changes shape, increasing affinity for oxygen.
Deoxyhemoglobin has a relatively low affinity for O2. As it begins to load up with Oxygen, the affinity for
oxygen increases. Hemoglobin in its oxygenated state has a higher affinity for O2.
When the hemoglobin leaves the lungs and goes to the body, we see the reverse effect. The
hemoglobin gives up its oxygen. The shape changes in a lower oxygen environment reducing affinity
for oxygen and causing oxygen to be delivered.
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The relationship between the transfer of O2 and the amount of O2 in the environment is shown in the
oxygen disassociation/association curve.
The partial pressure of O2 (ppO2) - this is a measure of how much O2 is available in that particular
environment.
The air that you breath is 20% O2. So if the pressure of the air is at 760 mm Hg, then the pp will be
around 152 mm Hg. Since the air in the lungs is saturated with water and water takes up some of that
the actual value is around 110 mm Hg.
The curve expresses the level of saturation of hemoglobin based on the amount of O2 in the
environment.
It is S shaped. When hemoglobin is in the lungs, it will saturate, but when it goes to a tissue, it drops,
and will deliver O2.
November 2nd
p4
The oxygen dissociation curve
The crucial factor is AFFINITY. The greater the affinity the less oxygen it takes to load that pigment up.
There is a price to pay though. but before we go there - As the tissues and the blood plasma pH
becomes more acid, hemoglobin affinity is reduced. Since that acidity is going to happen in the tissues.
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That means that the tissue that's more acid will get more oxygen. Blood goes heart, lungs, heart,
tissues. When it goes through tissues it only goes through one set of capillaries. It comes to the tissues
loaded with oxygen. The more acid the tissue, the more the hemoglobin unloads oxygen. The tissue
becomes acid due to the production of CO2, which leads to Carbonic acid formation.
Hemoglobin loads up at a PO2 of about 100.
In the muscles there is a molecule called myoglobin, which is very similar to one of the chains in
hemoglobin. It only has one heme group. When we look at the oxygen dissociation curve of myoglobin
we see that it loads up at a lower PO2 than Hemoglobin. So when hemoglobin unloads O2, myoglobin
readily takes it up.
*hemocyanin has an oxygen dissociation curve like myoglobin. It has a High affinity for oxygen. So this
pigment has an easy time picking up oxygen, but a hard time delivering it. The tissue PO2 has to be
very low**
The top graph shows different animals with hemoglobin as there respiratory pigment. But they have
different affinities for Oxygen. Mice have high metabolic rates. They burn oxygen much more rapidly
than we do. Animals that live at high altitudes have an oxygen dissociation curve shifted to the left. This
means it loads up with oxygen more easily, but can't be as active because they have to create low PO2
in there tissues.
A mouse living at high altitudes will be to the left. It needs to load up easily. It can't be as active. I you
find an organism of the same species living at sea level, the curve will be shifted to the right. This
means that there is an important adaptation that occurs that depends on Oxygen availability.
*The hemocyanin of the horseshoe crab has a reverse bohr effect. Increasing acidity makes the
pigment have a high affinity for oxygen.*
p5
CO2 - Here is the problem.
CO2 + H2O <--> H2CO3 <--> H+ + HCO3This causes pH to decrease and then you're dead. So what we are going to do is look at how CO2 is
transported.
We have CO2 going into the blood and Oxygen going into the tissue. The first reaction that happens is
that 7% of the CO2 that we produced goes to the reaction above leading to the production of Carbonic
acid. The blood buffers are good enough to handle that much carbonic acid. This stays in the plasma.
Now, 70% of the CO2 goes through the following reaction inside the red blood cell forming H+ and
HCO3- by the enzyme Carbonic anhydrase. Hemoglobin to the rescue. When oxyhemoglobin (HbO8)
releases O2, it picks up protons. In this case, hemoglobin is the buffer. There is a problem here.
The bicarbonate will go through the RBC membrane out to the plasma. This will increase the charge
across the membrane. This will stop bicarbonate from leaving if there isn't a savior.
When bicarbonate leaves, Cl- comes in and takes care of the charge. This is called the chloride shift
and depends on specific permeases for Cl- and bicarbonate ion. This process of transport can then
continue.
- The other 23% --> CO2 + Hb (deoxyhemoglobin) <--> HbCO2 (carbamino hemoglobin). It never forms
carbonic acid.
WHEN YOU GET TO THE LUNGS WE GET THE REVERSE.
(new handout)
RESPIRATORY SYSTEM
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I. Respiratory Exchange - Exchange of gases between organism and environment.
A planaria is a flatworm. It does not have a respiratory system. Because it's flat and thin, all or the cells
are close enough to the environment. This is really all that we need for a respiratory surface.
A. Respiratory surface
1. Has to be large in terms of surface area.
2. It has to be moist - Gas exchange happens in solution
3. Has to happen near active cells - cells that are using oxygen and producing CO2
November 2nd (cont)
The respiratory surface of both lungs is about the size of a tennis court. That's big.
Why not just put it on our back? Because moisture loss would be too big.
Our lungs are inside the body. In place of being near active cells, we have to add a circulatory system.
This respiratory area has to be highly vascular so that the blood is not very far away from the air.
The air that we breathe out is typically saturated with water.
B. When we have an internal respiratory organ, we have to have a mechanism, there has to be a
pump associated to move gases in and out.
II. Human respiratory system - We have 3 spaces to be concerned about
A. Lungs - elastic/stretchy. This is because of elastic connective tissue and because of a little bit of
smooth muscle. But clearly the lungs can't be a muscular organ like the heart that themselves contract
and expand. So we have to have an elastic lung that is very thin and facilitates gas exchange.
1. Cavities:
- Intrapulmonary: inside the lungs. It is open to the atmosphere all the time.
- Thoracic cavity: The whole cavity that contains the lungs and heart. It is sealed.
- Pleural cavity: Bounded by the pleural sac. This sac has 2 layers: A parietal layer that lines the
thoracic cavity and a visceral layer that covers the lungs. The pleural cavity is the space that's shown
as white in the diagram. It is fluid filled, which acts as a lubricant.
When we start the respiratory process, we will see that the respiratory movements reduce pressure in
thoracic cavity, which reduces the pressure in the pleural cavity, causing the lungs to expand because
of the greater atmospheric pressure.
November 5th
3 Cavities:
- Pulmonary - open to atmosphere
- Thoracic - sealed. Bounded by the body wall in the diaphragm.
- Pleural - within the pleural sac. It is fluid filled. Immediately surrounds the lungs
Breathing involved an active change in the volume of the thoracic cavity, reducing and increasing its
pressure. We are going to see how that happens. But before that, lets look at the actual structure in the
lungs that supports gas exchange.
- Trachea - main airway between the mouth and the lungs.
- 2 major bronchi - large tubes, one going to each lungs.
- Bronchioles - small tubes
- Alveolar duct
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- Alveolar sac - terminating the duct
- Alveoli - where the major gas exchange happens
The alveolar duct and sac are covered with a capillary network. The blood gets oxygenated and goes
back via the pulmonary vein to the heart.
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p3
The lungs are elastic. The pressure changes that occur for the process of respiration are created in the
thoracic cavity. Lets look then at the processes that cause you to breathe in and out.
PRESSURE CHANGES DURIN RESPIRATION
If there is going to be pressure changes in the thoracic cavity there has to be volume changes.
Thoracic cavity pressure changes
- Diaphragm: Boundary between the thoracic cavity and the abdominal cavity.. The diaphragm is kind of
oval shaped. It is a band of muscle, and there is central connective tissue, which is strong but noncontractile. Its position at rest is domelike.
- Thoracic cavity wall: The external intercostals - These are involved in inspiration. The internal
intercostals - These are involved in expiration.
Eupnea - normal/quiet breathing.
- Inspiration has to result in a reduced thoracic cavity pressure. So making the cavity larger does this.
The cavity is made larger by 2 sets of muscles:
1. The diaphragm contracts
2. The external intercostals contract.
Both of these will enlarge the volume of the thoracic cavity, which reduces the pressure in the pleural
cavity, which means then that the pressure in the pulmonary cavity (atm) is greater than the pressure in
the pleural cavity, forcing the lungs to expand.
2. Expiration - passive. The diaphragm relaxes, the external intercostals relax.
* When diaphragm contracts, this reduces abdominal cavity space, increasing the pressure. When it
relaxes, the abdominal organs push the diaphragm back into place. Muscles can't extend. It can just
relax and be "stretched".*
When thoracic cavity pressure goes up, pleural cavity pressure goes up above pulmonary pressure,
and that forces air out.
Why don't the lungs collapse at the end of an expiration?
- The lungs are very elastic. This means that after we have expiratory movements, the lungs continue
to become smaller. This reduces thoracic cavity pressure below atmospheric. If the pressure in the
thorax, and thus the pleural cavity, increases, this keeps the lungs from getting too small.
- Surfactant - released by special cells in the lungs that reduces surface tension of water. Part of the
constriction of the lungs is the combined effect of surface tension and elasticity.
Dyspnea - forced breathing.
- The inspiratory phase is the same as Eupnea with two additional muscles connected to the clavicle
(neck muscles).
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- The expiratory phase is different. It involves the internal intercostals and the abdominal musculature.
The internal intercostals pull the rib cage down. The abdominal muscle contract force the diaphragm up
by increasing abdominal pressure.
What happens if and of the walls of the thoracic cavity are penetrated?
This is called a Pneumothorax, and that happens as a result of trauma. This means that the individual
cannot breathe. When the diaphragm contracts, it simply sucks air though the hole in the wall.
Fortunately, the 2 lungs are separate, so if only 1 lung collapse, you can use the other one. When you
have a bilateral pneumothorax, breathing is no longer possible.
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There is intimate contact between a capillary outside of the alveolus and the alveolar space.
p5
You have interpleural pressure changes that are the result of changes in the thoracic cavity pressure.
This pressure is enough for normal inspiration and expiration to happen.
The average person is breathing in 1L of air at rest.
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There is a coupling between ventilation perfusion and
In regions of high airflow, the resulting PO2 causes the arterioles to dilate so blood supply increases.
When airflow through a bronchiole is high compared to its blood supply, CO2 levels drops and the
bronchioles constrict reducing the blood flow. (See handout for proper explanation)
Lecture Notes for System Physiology. Part III
The Urinary System (incomplete)
November 16th
p1
Marine alasmobranch. They live in environments with not enough water (in ocean). This is because the
ocean water is too hypertonic. There are a variety of solutions to this. One is regulators/conformers. A
lot of invertebrates are conformers. When we get into vertebrates we have interesting solutions. Very
few are isotonic with their environment, but many of the cartilaginous fish are.
Urea is one of the forms to get away nitrogen. Alasmobranches stores urea in the blood plasma that
makes them isotonic with the seawater. This raises their osmolarity. Urea is toxic, but they have detox
mechanisms at the cellular level.
Marine teleost. They drink seawater. But they have to get rid of ions because its blood concentration is
hypotonic. They have active pump that pumps ions back to the seawater across the gill. The kidney is
not highly developed and waste is secreted directly into the kidney tubules. They produce a very small
amount of urine.
Freshwater fish have the opposite problem. Their environment is too dilute. They have to keep their
blood concentration hypertonic. They produce a large amount of urine that is very dilute. They have
pumps that pumps ions across the gill into the water.
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Marine birds feed on the organisms in the water. Their solution is like the marine fish except they have
salt glands that pumps salt out. This is a very concentrated salt solution.
p4
Desert animals. There are several mechanisms. They reduce the amount of water loss through
expiration. Their water content of expired air is very low. There is very little water to dink so they get
metabolic water. They conserve water so carefully that they can get by on metabolic water. That is
water produced by respiration. They produce very little urine that is very concentrated, and they
produce feces that is very dry.
p3
How do you get rid of waste products?
- NH3. These animals must produce a large amount of very hypotonic urine. That means that they need
a lot of water. Because Urea is very toxic, so we can't afford to let the ammonia level in the blood
increase.
- Urea. This is moderately toxic. So there is going to be a modest amount of urine produced. In humans
that modest amount is 1L/day. However, there is a cost for getting rid of your waste produces as urea.
The urea cycle happens in the liver. This costs energy. This is the way we detoxify ammonia and get rid
of it in the form of urea.
- Uric acid. Animals don't need very much water. They produce little urine. It is crystalline and is not
eliminated in solution. It is simply released as crystals. It is more complex than urea to make, but we
are not going into it. This costs even more energy in terms of producing the waste product.
*As the need for energy goes up, the need for water goes down*
p2
Nitrogen excretion by different vertebrate groups.
- Ammonotelic organisms produce ammonotelic.
- Ureotelic organisms produce urea
- Uricotelic organisms produce uric acid.
(new handout)
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THE EXCRETORY SYSTEM
Excretion
I. The purpose is to maintain "proper" makeup of internal content. We want the right stuff inside, and we
want to get rid of what we shouldn't have. This is a very important part of homeostasis.
A. A very important part of this process is getting rid of waste.
1. Wastes - products of metabolism:
- Protein --> Transformed into amino acids. When amino acids are metabolized we get CO2, H2O +
NH3.
- Carbohydrates and fats --> Broken down to CO2 + H20.
- CO2 --> Handles via the respiratory system. However, CO2 produces Carbonic acid and the excretory
system is involved in getting rid of excess acidity. CO2 is not the only source for this acidity, but is
certainly the primary one.
2. NH3 - This is really very toxic. NH3 --> urea (via the urea cycle)
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B. There is another very important process in the excretory system and that is getting rid of
substances that are in excess. In place of breakfast if we get 2 milkshakes. On the way to the doctorʼs
office, the doctor takes a urine test. If you don't tell him about the milk shake, He will think you have
diabetes. The kidney processes a huge amount of blood and produces a lot of substrate. Everything
that goes through your kidney and does not go back to the blood comes out as urine. Approximately
200L filtrate goes through the kidney per day, and the kidney produces 1L. The difference is
reabsorption.
One of the most painless ways of committing suicide is by sticking KCL in your veins. This raises the K
levels, and then neurons depolarizes and the first thing you will die from is your heart stopping because
the SA node will be continuously depolarized. This shows that regulation is really important.
II. Human Kidney
A. Anatomy - There are 3 major areas:
1. Cortex - outer layer. Involved in processing.
2. Medulla - Middle layer. Also involved in processing.
3. Pelvis - Involved in collecting urine.
B. Blood supply
Cardiac output for an average individual is about 5.6L/minute of this cardiac output, what goes to
the kidneys is 1.2 L/minute. That is roughly 20% of cardiac output. These are figures at rest. During
exercise the fraction going to the kidneys goes down.
Of this, 125ml/min forms filtrate. This is about 10% of blood volume going to the kidneys. This means
that the total processing of filtrate is about 180L/day. The process of reabsoption drops this down to 1L/
day of urine. So the kidneys are richly supplied with blood and are processing the blood all the time.
C. Nephron - The processing unit. The nephron is made up of a renal corpuscle. The renal corpuscle
is made up of Bowmanʼs capsule and the glomerulus. This nephron is also sometimes called a kidney
tubule. The function here is filtration. Then we have the proximal convoluted tubule. It is involved in
small molecule and water reabsorption. The loop of Henley is involved in water reabsorption. The distal
convoluted tubule is involved in Ion reabsorption (Na, K) and H2O
D. Collecting duct - H2O reabsorption + urine production.
p2
There is 1 additional feature at the level of the nephron that we need to look at and that is the details of
how blood is supplied.
- Interlobular artery: Comes from the arcurate artery, which is a branch of the renal artery. The
interlobular artery branches into the afferent arteriole. Afferent meaning going toward the glomerulus.
This is a not of capillaries. This is where filtration happens. When the blood leaves the glomerulus it
goes back to the efferent arteriole, and then we have another capillary bed called the peritubular
capillaries. These are the capillaries that surround the nephron. Notice that the blood in the peritubular
capillaries has come through the glomerulus. Then the blood goes from the peritubular capillaries to the
interlobular vein.
Summary: The major processes are filtration, reabsorption and secretion, and Elimination of urine. This
is really summarized on p3.
November 19th
p4
III. Filtration
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A. Anatomy of renal corpuscle: includes 2 major constituents
1. Bowman's capsule.
- Parietal layer - cuboidal epithelial. This gives you the "outer wall"
- Visceral layer - thin cells. Surround glomerular capillaries.
- Capsular space - Space between the outer and in walls. This is where filtrate is collected.
2. Glomerulus
- Afferent arterioles - They vasoconstrict and vasodilate. They are very reactive arterioles. They lead to
the glomerulus.
- Efferent arteriole - Takes blood away from the glomerulus. Has a narrower diameter than the afferent
arteriole.
The Glomerulus is a knot of capillaries within Bowman's capsule that is surrounded by the visceral
layer.
3. The filtration membrane - Endothelium of the glomerulus. There are rather large "pores"
- Basement membrane of the visceral layer.
- Podocytes - Cells of the visceral layer that surround the glomerular capillaries. They have a very
special way of connecting with each other and it is called pedicels - interconnection with adjacent
podocytes. They provide space for filtration.
The filtration membrane is a combination of the endothelium, the basement membrane and the
pedicels. Proteins up to 70,000 mw can get thru. Proteins with a mw of 5,000 has a little barrier.
The glomerulus is a rather porous set of capillaries with a backpressure due to the difference in
diameter of the efferent and afferent arterioles.
p5
B. Filtration
1. Net filtration pressure - The force for filtration is the blood pressure. That, in the glomerulus is 60 mm
Hg. That is the hydrostatic pressure inside the glomerulus. This is the force for filtration. In the capsular
space we have a pressure of 15 mm Hg. That is subtracted away. There is also osmotic pressure
because of lack of big proteins that are in the plasma. So water will be more concentrated in the
capsule. Water will move in due to osmosis. The osmotic pressure is 28 mm Hg. This is also
subtracted. The net filtration pressure will be 17 mm Hg. That is 60 - 15 - 28. So we have a net filtrate
of 180 L/day.
*We can easily get by with 1 kidney, because the kidney do work very well*
Reabsorption is taking stuff out of the filtrate and putting into the blood.
Blood goes into the glomerulus and then goes to a network of capillaries that surround the tubules. The
peritubular capillaries have blood that has gone through the glomerulus.
IV. Reabsorption - Proximal convoluted Tubule (PCT).
A. Anatomy:
The cells are cuboidal. There are some spaces and some membranes that we need to know:
1. Lumen - space
2. The luminal membrane - The membrane of cuboidal cells that line the lumen. The cells have a very
well developed brush border. These are individual finger-like extensions of the luminal membrane.
3. Basolateral membrane - The other membrane of these tubule cells. This bounds the tubule. It is the
outer membrane
4. Interstitial fluid/peritubular fluid - surrounds the basolateral membrane
The peritubular capillaries are immersed in the interstitial fluid.
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Reabsoption is going to go from filtrate in the lumen across the luminal membrane across the
basolateral membrane into the interstitial fluid and from that into the capillaries.
p6
Reabsoption pathways:
1. Transcellular pathway - The stuff has to go across the cellular membrane. This is active movement.
2. Paracellular pathway - The stuff goes between cells. This is passive. Major pathway for water and
other stuff.
p7
Trans cellular
- basolateral membrane
We have the basolateral membrane. 1. We have the NA/K pump. The Na is going out to the interstitial
fluid, and K is coming into the cell. The result of this active process is keeping the NA concentration in
the cell low and high in the interstitial fluid.
2. We also have a passive K channel. This causes K to go out by diffusion. This negates the effect of
Na/k pump. THIS MEANS THAT THE OVERALL EFFECT OF THE NA/K PUMP IS TO PUMP NA OUT.
November 26th
PCT cont
Materials that are reabsorbed have to move from the filtrate, through the cellular layer, to the interstitial
fluid, into the capillaries. We have a luminal membrane (lines the lumen) and a basolateral membrane
(adjacent to the interstitial fluid). This is the Tran cellular reabsorption pathway with a net result of Na
out.
There are also glucose channel in the basolateral membrane. This is facilitation. Glucose goes down
the concentration gradient. Glucose goes by facilitative diffusion out the cell.
The Na/K pump is the only active process, and provides the driving force for everything else that
happen.
The intracellular Na concentration is being kept low.
THE LUMINAL MEMBRANE - the membrane lining the lumen of the kidney tubule.
- The intracellular concentration of Na is low. There is a Na-glucose cotransport permease. This uses
the energy from Na diffusion down its concentration gradient into the cell. Glucose is actively
transported, and the energy for that concentration is the Na gradient. The filtrate can be completely
cleaned of glucose. This causes the intracellular concentration of glucose to be high, and then it can be
transported against its concentration gradient out to the peritubular fluid. This way we can get glucose,
which is the good stuff, back into the capillaries and to the body.
Under normal conditions, none of the good stuff is left. This process is so good.
- There are also passive Na channels in the luminal membrane. The Na/K pump in the basolateral
membrane is so good that we want to get as much Na out of the lumen. This also helps for water
movement, because water is never actively transport.
- H+-Na+ antiport. This is a way of controlling the acidity of the blood. It uses the energy of a Na going
into the cell to transport H+ out of the cell into the filtrate lumen. This is a major mechanism of pH
control and is called SECRETION. This is for substances taken out of the blood after the glomerulus
and put into the filtrate. *H+ ions move across the basolateral membrane down its concentration
gradient.*
- There are proteins in filtrate. The proteins are reabsorbed by a concentration of endocytosis in the
luminal membrane and exocytosis in the basolateral membrane.
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- The water concentration in filtrate is getting higher and higher. There was already more water than in
the blood after filtration in the glomerulus, it just gets higher and higher.
Paracellular pathway
- H2O reabsorption
Cells of the tubule are held together by tight junctions. However, it is a pathway that water uses. Water
in the lumen (filtrate) is in a higher concentration that in the peritubular space. Water will move by
osmosis from the lumen, across the paracellular pathway, to the interstitial fluid. Ions also follow the
water because as water moves through the pathway, the ion concentration becomes greater in the
lumen and follow along their concentration gradient. The net result of this process is that approximately
70% of water in filtrate is reabsorbed in the proximal tubule.
IN THE PROXIMAL TUBULE ALL OF THE GOOD STUFF AND 70% OF WATER HAS MOVED INTO
THE BLOOD.
(next handout)
Rest of the tubule - H2O + ion reabsorption.
Loop of Henley:
- Descending limb. In the medulla we have a gradient of NaCL that is smallest in the cortex and
greatest in the lower part of the medulla. This means that water concentration goes down as the ion
concentration goes up. The cells in the descending limb are very thin. There are essentially no ion
channels. Ions can't move across the membrane without channels. The descending limb does not allow
ions to move across the membrane. But water moves rather freely. As fluid moves down the loop, it's
facing an extracellular medium that has less water in it. Water will continue to leave as it moves down.
At the bottom of the descending limb, the filtrate will have less water, but no ions have come in.
p3
- Ascending limb: The cells are very different than the descending limb. Here, the cells are cuboidal.
The cells and the paracellular pathway are impervious to water. Water can't come back in.
- Luminal membrane:
1. Na, Cl, K permease. This is a cotransport of 3 different ions. Na gradient drives this process.
There are also passive Na and K channels. Ions are being taken out of the lumen and put into the cell.
At the bottom of the loop of Henley the ion concentration is high. Water goes out the most at the top of
the descending limb, and ion goes out the most at the bottom of the ascending limb, and Na creates
it's own gradient.
- Basolateral membrane:
1We have the Na/K pump doing just what it did before. Pumping Na out and K in. But the net result is
Na out due to K channels.
2. We also have a Cl channel. With the K channel letting K go where ever it wants to, the charge
across the basolateral membrane is getting positive on the outside due to Na leaving. Cl will then follow
because of that charge and Cl will follow freely behind Na.
- The tight junction of the paracellular pathway is covered with a glycoprotein that prevents water
movement. The paracellular pathway is blocked.
THE NET RESULT OF THE ASCENDING LIMB IS IONS MOVING OUT.
November 28th
The early distal convoluted tubule. Na/K pumps on the luminal membrane, but water cannot pass.
(same as ascending loop).
What we've done up to now is what happens all the time, now we are going to look at the part of the
kidney where we regulate the amount of urine.
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- 10 -
p4 + 5
C. Late distal convoluted tubule and the cortical collecting duct (CCD)
- There are 2 types of cells:
1. Intercalated cell - It secretes H+ ions into the filtrate. The mech is the same as in the proximal
convoluted tubule - Na/H antiport.
2. Principal cells - where control actually takes place. Initially they don't look all that special. NA/K
pumps in the basolateral membrane and pumps Na out (net). The luminal membrane is still impervious
to water. These principal cells are under hormone regulation. The hormone secreted by the adrenal
gland is aldosterone. When it is secreted we added additional NA/K pumps to the basolateral
membrane (genetic upregulation). This means that the effect of aldosterone is to increase Na transport
into the interstitial fluid --> reabsoption. This will favor water reabsorption. ADH increases Na
reabsorption. This creates a further gradient for water reabsorption.
A decrease in MAP is sensed by the afferent arteriole by a mechanism called the juxtaglomerular
apparatus (JGA). This causes an increased renin release (JGA). This increased renin release
transforms angiotensinogen into angiotensin one. Then the converting enzyme converts angiotensin 1
to angiotensin 2. This causes vasoconstriction. It also causes the adrenal cortex to release aldosterone,
and aldosterone causes increase Na reabsorption. This favors water reabsorption. This increases blood
volume, which increases MAP.
Less important pathway:
A major decrease in Na concentration in the blood or a small increase in K+ concentration causes the
hypothalamus to release the cortisol releasing hormone (CRH). This goes to the anterior pituitary,
which produces a hormone called Adrenocorticotropic hormone (ACTH), which causes an increase in
aldosterone production.
K+ channels are only in the luminal membrane (in the late DCT). This means that K+ is excreted/
secreted (goes into filtrate). This increase in K+ concentration will, as mentioned above, will increase
aldosterone levels. This regulates K+ concentration in the blood. If this is too high it will upset the
nervous system. This is a major protective mechanism.
There is one other pathway we want to stress:
Stress (behavioral) causes an increase in the release of CRH, which causes an increase in the release
of ACTH, which causes an increase in the release of aldosterone, which causes an increase in MAP.
The hypothalamus produces another hormone called the antidiuretic hormone (ADH - diuresis = urine
production). This reduces the amount of urine production, by increased water reabsorption. ADH is
released to the blood and its effect is on principal cells, in which there will be water channels integrated
into the luminal membrane (this is also a genetic effect).
A reduction in MAP is sensed by the hypothalamus, which will turn this mechanism on. Or if the MAP is
too high, then the hyp will decrease ADH release.
p6
D. The medullary collecting duct.
The filtrate is going back through the osmotic gradient. This will increase water reabsorption. This
reabsorption is also under the control of ADH. We still require water channels in the luminal membrane.
This is another region where the volume of urine production is regulated.
5% of filtrate makes it to the DCT and the processes we are talking about regulate how much of that is
reabsorbed.
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(pg 6+7 are ours)
p8 + 9
The Juxtaglomerular apparatus:
- Primarily involved in the renin - angiotensin mechanism. It surrounds the afferent arteriole. There are
macular densa cells and some other cells. The macula densa cells sense a decrease in Na
concentration and cause an increase in renin release.
The granular cells sense a decrease in MAP and cause renin release.
Sympathetic innervation also increases renin release. All of these cause renin release and will result in
an increase in MAP.
When filtrate comes out of the collecting duct its urine.
(Next handout)
Urea is the major nitrogenous waste in humans.
p2
Urea is largely left in the filtrate for excretion. This is the way we get rid of it. This graph shows the
concentration of Na,Cl and CL in the filtrate in different regions of the kidney.
November 30th
The more glucose in blood, the more will appear in filtrate. The x-axis is a function of the concentration
of glucose in the blood. It is assuming a certain filtration rate. What is important is the ability of the renal
tubule to absorb. The dotted line shows the appearance of glucose in the filtrate. As the amount of
glucose in the filtrate increases, reabsorption increases. Everything that appears in the filtrate is
reabsorbed until 200 mg %. The second line represents the excreted urine. The more glucose is in
filtrate, the more will be reabsorbed to a point. Reabsorption is an active process involving permeases.
Clearly, there is going to come a point where the reabsorption curve flattens because the transport
molecules are transported. This is the renal threshold - the concentration in filtrate at which glucose
begins to appear in the urine. When it reaches threshold, the excretion line is parallel to the filtration
line. This is a safety mechanism to ensure that blood glucose level doesn't get to high.
Excretion starts at the renal threshold and curves. At renal threshold there is still absorption, but not
100%. At transport maximum, all the permeases are saturated.
The elimination of fluid in the body is one of the most important long-term regulation mechanisms.
(next handout)
THE ENDOCRINE SYSEM
Hormonal regulation
I. Comparison with Nervous system messengers.
A. Chemical messengers.
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1. Hormone - a messenger that is released to the blood and whose target is distant. The hormone
is conducted from its site of release to its site of action via the circulatory system
2. Neurosecretory hormone - A hormone that is released by a nerve cell as a result of nerve
impulses, which are released from vesicles to the blood, and then finds a distant target. This definition
becomes difficult because many neurohormones are both released into the circulatory system and
released proximal to the target, which makes them "technically" not a hormone. (e.g. norepinephrine)
3. Paracrine - The cell released a controlling agent, which finds the target cell via local fluid.
4. Autocrine - the target is the releasing cell.
5 Target - Receptors define targets, messengers don't.
Hormone versus neural regulation:
- Neural: Regulation is quick and short in duration
- Hormonal: slower in onset and longer in duration
II. Mechanism of action
- The hormone is typically the messenger, the receptor defines the target, and the effect (mechanism of
action) is the result of receptor activation.
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The overwhelmingly common but not only mechanism is 2nd messengers. Amplification is another
common theme that is crucial for this system to work. The messenger can't carry out the action, it only
initiates it. The action results from amplification. the most common example is 2nd messenger.
(familiarize yourself with the bottom picture - didn't go over it in class)
p3
Target location is not always at the surface. Many of the hormones are nonpolar and can traverse the
membrane. e.g. steroid hormones. The receptors are internal, and the result is gene activation. This is
where amplification comes.
There is a protein in almost all cells produced by a gene, which is called CREB. This is called the
cAMP response element. When the protein is activated, it becomes a regulator for early response
genes. cAMP is produced by adenylate cyclase when receptor binds hormone. CREB binds to cAMP
and causes gene activation.
Possible effects of hormones:
- Renin is a hormone. It is released into the blood. Its target is angiotensinogen. Renin is an enzyme.
Hormones can be enzymatic.
- Cell permeability - insulin regulates the permeability of most of the cells in the body to glucose.
- Metabolism - Thyroid hormone
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III. Regulation of hormone production
A. Ion availability - e.g. Na levels in the blood --> release of renin
B. Level of nutrients - e.g. glucose and insulin.
C. Neurotransmitters and thus the nervous system
D. Other hormones
p5
Fates of hormones
- Can be excreted without having an effect.
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- Can be activated by metabolism - by liver. They become inactive and the excreted
- Can be delivered to target cell
- Can be activated my metabolism and the delivered to target cell
- Can catalyze the formation of active hormone from plasma protein. E.g. renin's affect on
angiotensinogen.
(next handout)
In vertebrates, the major control of many hormonal pathways is via the pituitary gland and nervous
system. The anterior pituitary is not produced by the nervous system. The posterior pituitary is. The
pituitary gland is intimately connected to the hypothalamus.
- The anterior pituitary
The hypothalamus releases releasing hormones or inhibitory hormones directly into a capillary bed in
the hypothalamus that reforms into a portal vein that reforms into capillaries in the anterior pituitary. The
hormones then regulate the anterior pituitary hormones.
December 5th
p1
Reproduction - Hormonal control
I. Gonadotropins
A. FSH - stimulates production of gametes
- inhibin - inhibits production of FSH
B. LH - stimulates production of sex hormones
- testosterone - male
- estrogen - female
II. Male
A. LH - targets leydig cells in the testes (interstitial cells). These cells produce testosterone
B. Testosterone is the hormone, which creates "maleness", in terms of body form, distribution of fat,
muscle location, increase in muscle size, hair distribution etc.
C. FSH (+ testosterone) stimulates the sertoli cells, which produce sperm. Sperm are produced
within the seminiferous tubules, and the sertoli cells are in the progenitor layer. The sertoli cells also
produce inhibin, which gives a negative feedback on the anterior pituitary for producing FSH. There is
no cycle in the male in terms of the function of hormones as in the female.
p2
III. Female
The process is superficially fairly simple, but there are much more complex interactions within the
various hormones.
- FSH - promotes the maturation of the graafian follicle. The graafian follicle contains a single ovum.
The ovary simply "decides" which follicle is the next one to produce a ovum. Within the GF there are
granulosa cell, which are specifically involved in the maturation process. These are the specific targets
of FSH. This is the preparation for ovulation.
After ovulation, FSH (with LH) also promotes development of the corpus luteum.
Inhibin also causes a negative feedback on the production of FSH.
- LH - targets the theca cells, which produce androgens. These are precursors of either the male or
female sex hormones. Granulosa cells then process these androgens, and the results of that is the
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production of estrogen. Estrogen has a negative feedback effect on the hypothalamus an anterior
pituitary (effecting primarily LH)
The targets of estrogen are the female specific development - breasts, etc.
At certain phases it can cause positive feedback on its own production. At certain phases it can also
cause positive feedback on the production of LH.
After ovulation, under the influence of LH, we have the graafian follicle transforming into an endocrine
structure called the corpus luteum, and is now the source of a secondary sex hormone called
progesterone.
p3
We have an ovarian phase and a luteal phase.
To understand the cycle, you have to think about things moving along on a day to day basis, with there
being some delays in what happens.
FSH stimulates production of estrogen. But there is a point when FSH level goes down, and estrogen
levels continue to rise. This is the phase where estrogen self stimulates its own production. FSH levels
are being repressed because of increase in estrogen levels.
C. Monthly cycle - we typically time the monthly cycle as beginning on the day following the end of
the menstrual flow.
Day 1 - estrogen is low. FSH is increasing. Progesterone is low. LH is low.
1. Since FSH is increasing, this starts an increase in estrogen. As estrogen goes up, it causes a
decrease in FSH production. But there is also the feedback effect on causing more estrogen
production.
2. The decreasing FSH + the increasing estrogen are the primary cause for the sudden increase in
LH. (This causes a small increase in FSH.). This leads to the LH spike. That spike precedes ovulation.
The LH spike is the primary cause for ovulation. The LH transforms the graafian follicle into the corpus
luteum (The graafian follicle fills in with cells and becomes the corpus luteum). The corpus luteum
becomes the primary source of progesterone. Progesterone + estrogen together cause a proliferation
of the uterine wall. This means that the epithelial tissue increase and becomes filled with capillaries.
This proliferation prepares the uterine wall for implantation. If the egg is fertilized, it goes through
several days of development before it implants.
So high estrogen and progesterone gives us uterine proliferation. At this point, the high estrogen and
the high progesterone cause the depression of both FSH and LH. This causes a decrease in estrogen
and a decrease in progesterone, and that causes the breakdown of the uterine wall, resulting in
menstrual flow. Ovulation usually occurs at about day 14.
Fertilization has taken place. Then we get embryonic development, and then we get implantation.
Implantation causes a development (very quickly) of a membrane we call the placental membrane. It is
really 2 sets of capillaries that are right next to each other that support exchange of material between
fetal and maternal circulation. It also begins to secrete, in large amounts, and FSH and LH-like
hormones. They are not under the control of negative feedback. If implantation occurs, there will be
another source of FSH and LH, and these will promote prolonged high increases in estrogen and
progesterone.
p5
The FSH and LH like hormones are together known as the chorionic gonadotropins. They will also
suppress the production of FSH and LH from the anterior pituitary so we no longer get the cyclical
productions of its own natural FSH and LH.
Pills are mostly progesterone, which stops LH, thus no LH spike and thus no estrogen.
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p6
H. Hormonal regulation of nutrients in blood.
I. Pancreas - beta cells
A. Islets of Langer hans produce insulin.
B. Factors that increase insulin production and release
1. Increase in blood glucose. all of the blood coming back from the digestive system does not go
directly to the heart. there is a hepatic portal system in which the blood goes into another set of
capillaries, which is in the liver. It goes from those capillaries into sinuses in the liver. This is where
nutrients that had been dumped into the blood by digestive system are taken out before the blood goes
back to the heart. The storage in the liver is intimately under insulin control.
2. Increase in blood amino acids
3. Increase fatty acids.
4. Insulineotropic hormone. This hormone is gastrointestinal. Cells in the lining of the digestive
system produce this hormone, which then increases insulin release.
5. Autonomic effect. Increased sympathetic activity reduces insulin release. Increased
parasympathetic activity increases insulin release.
p7
Effects of insulin - very pervasive
- One dominant effect is that it increases movement of glucose across the plasma membrane. This
does not apply to the brain or heart.
In most cells we have a glucose transporter. these are sequestered inside on vesicles. We have a
receptor on the membrane for insulin. The glucose transporters on the membrane are not very effective
in the absence of insulin. when insulin becomes available, it causes a change in the glucose
transporters in the membrane, and it causes the fusion of the intracellular vesicles with the plasma
membrane. This will enhance permeability to glucose. When insulin becomes less available, we get the
opposite.
p8
The things that insulin does.
Actions of insulin:
1. Insulin promotes the synthesis of proteins from amino acids. It promotes the synthesis of fats from
fatty acids and glycerol. Problems with insulin are often associated with problems in obesity. It also
promotes the synthesis of glycogen from glucose.
Insulin tips the balance towards using glucose for energy. You are less likely to use fats.
3. In the liver, insulin promotes the synthesis of fat and glycogen from glucose.
Low levels of insulin - blood levels of glucose are falling.
- Promotes utilization of fatty acids and ketones.
- Promotes the transformation of pyruvatte etc. into glucose in the liver.
p9
Alpha cells produce glucagon. Glucagon mobilizes the availability of glucose in the blood, so that
between meals when blood glucose begins to drop, glucagon facilitates the break down of glycogen.
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