Lecture 16

 
 

• Plasma Globulins, Continued
  
  • Beta 1 - ₁
    
    • ₁ – Haemopexin – it binds Heme group (not hemoglobin) – should the heme unit break off, Haemopexin will bind it, and then the liver will take up the whole thing.
      
    • ₁ – Transferrin – is an iron carrier in the blood, there is no free iron in the blood.
      
      • When we are absorbing iron, it will be taken by transferrin to be taken to where it is utilized – to make heme.
        
    • ₁ - C₄ – Complement Factor – we will learn more about this when we talk about the Immune System
      
  • Beta 2 - ₂
    
    • ₂ – Lipoprotein – (IDL (Intermediate Density Lipoprotein) and HDL (High Density Lipoprotein = this is the Bad Cholesterol)
      
    • ₂ – C₃ – Complement Factor – most prevalent complement factor
      
    • ₂ – Angiotensinogen – is the blood protein that renin would break off parts of it to create Angiotensin I, going to the ACE enzyme, and form Angiotensin II, it is a powerful protein for raising your blood pressure
      
    • ₂ – Plasminogen – it functions in blood clotting
      
  • Gamma - 
    
    • - Fibrinogen – it is activated by Thrombin to start making a clot
      
    • - Ig-A – Immunoglobin
      
    • - Ig-M – Immunoglobin
      
    • - Ig-G – Immunoglobin
      
      • The above three are Immunoglobins, and they carry on the immune response.  Immunoglobins are antibodies in various forms that can stimulate something to be produced.
        
      • Gamma globulin shots are used when we take a blood protein from someone who has antigens, and we give it to someone else who does not have these antigens so that that person can fight off an immune response
        
• Blood Clotting:
  
  • http://en.wikipedia.org/wiki/Coagulation
    
    
  • Platelets are very important for blood clotting.  They have small packets of granules, and they contain 3 types of granules:
    
    • Alpha - Granule: contain:
      
      • Albumin
        
      • Growth Factor called Platelet Derived Growth Factor
        
      • Clotting Factors
        
    • Delta - Granule: contain:
      
      • Serotonin – extremely powerful vasoconstrictor (if one is bleeding, we want to vasocontrict to stop the bleeding)
        
      • ADP (Non-metabolic) – it is acting as a signaler (it is not taking part in metabolism)
        
      • Catecholamines
        
    • Lambda - Granule: contain:
      
      • Lysosomal enzymes – (they are lysozymes) can attack bacteria and digest parts of their walls.
        
  • When there are no damaged vessels, the platelets circulate through the blood without sticking to anything.
    
  • In a damaged vessel there is exposed collagen, and when the platelets come into contact with Collagen, ADP, or Thrombin it is going to be activated.
    
  • Clotting is a Positive Feedback System, so there have to be mechanisms to shut it off so it does not get carried away with itself.   Clotting is a series of Positive and Negative Feedback systems.
    
    • Platelets are activated by collagen, ADP, and thrombin – tends to be a Positive Feedback System.
      
    • The activated platelet cell has a thickened outer layer that grows spikes (called Pseudopodia) – the layer is so thick that you cannot travel through it so the granules discharge and travel through the Canaliculi – the holes of the Canaliculi are where the Pseudopodia form.
      
    • The activated platelets will start to stick to other activated platelets and they will also start to stick to the area of the injury.
      
      • They will keep sticking together until they get a fairly large glob of platelets this is called a Platelet Plug.
        
        • The formation of this Platelet Plug is the first step in blood clotting.
          
        • These Platelet Plugs alone can stop blood loss in small vessels and capillaries (ex. Flicking someone can break capillaries and vessels)
          
    • Platelets release a Prostaglandin called Thrombaxane A2 – it acts for 30 seconds, which causes aggregation of platelets and vasoconstriction. This is a Positive Feedback System.
      
    • At the same time, endothelial cells release a Prostaglandin called Protacyclin – it acts for 2 minutes and prevents platelet aggregation/prevents clotting. This whole idea is that it limits the size of the Platelet Plug to the injury site, allowing other vessels to stay open and function.
      
    • This is how Aspirin works, it interferes with Prostaglandins. When you take the aspirin you are interfering with both, but since Protacyclin is produced by a cell, the cell recovers more quickly so more of it is produced. Thrombaxin A2 takes longer because it has to be replenished from the Megakaryoblast, and new platelets must be made. Aspirin acts as an Anti-coagulant and thins the blood.
      
  • Damaged blood vessels constrict:
    
    • Damaged blood vessels vasoconstrict in response to Serotonin.
      
      • People who slit their wrists very rarely die because the vessels will close right off.
        
    • Constriction is due to:
      
      • Pain
        
      • Smooth muscle injury
        
      • Damaged Endothelial release factors that cause vaso-constriction.
        
      • Platelets release a lot of factors too.
        
  • Clot Formation – you don't need to memorize the stair step, but know what is said about the stair-step.
    
    • There are lots of roman numerals.
      
    • The numbers are meaningless – they did not name them in the order that they worked into the stair step, they named them in the order they were discovered, you get jumping around.
      
    • Stair-Step Reaction will occur when you need a large clot.  Clotting happens with larger injuries.  The fundamental reaction is:
      
      • Fibrinogen (soluble in plasma, water soluble)  changes to Fibrin (insoluble protein, makes loose strands).
        
        • After the strand form we get Covalent Crosslink between the Fibrin strands, which are referred to as Stabilization.
          
        • The plasma will become gel-like when it comes in contact with the Fibrin fibers – it will entrap blood cells and be like a gelatinous mass (it looks reddish b/c there is cells inside).
          

          There are 2 factors:
    

    • Extrinsic factor – is an enzyme called Thromboplastin – it is released by damaged tissue – it activates Factor VII (part of the stair-step).  It is called a factor b/c it comes from outside of the blood and is released by damaged tissue.
      
      • Factor VII activates Factor X or IX of the stair step.
        
    • Intrinsic factor – is Factor XII – it gets activated – which activates the stair-step mechanism, but also activates proteins that activate Factor XII – this is a Positive Feedback Mechanism.
      
      • If you pull blood out of a vein and put it in a glass tube it will clot.  But it is not making Thromboplastin.  The cause of this is that the blood touches glass or collagen and it activates itself.
        
    • Both Extrinsic and Intrinsic pathways will lead to a blood clot.
      
    • Both pathways of blood clotting starts with Prothrombin changing to Thrombin.
      
      • Thrombin causes Fibrinogen to change to Fibrin
        
      • It also activates Factor XIII
        
      • The activated Factor XIII causes Stabilization of the Covalent Crosslinks to form.
        
    • There is a circulating blood protein protease inhibitor called Anti-thrombin III – it prevents blood clotting formation (by blocking Thrombin) in non-injured vessels.
      
    • Dissolving Blood Clot: getting rid of the clot – Clot Lysis
      
      • All endothelial cells, except for those in the brain (in the cerebral microcirculation), produce Thrombomodulin (it is stuck at the surface of the endothelial cell – it is not released).  When Thrombin binds to Thrombomodulin, it activates Protein-C (a blood Protein).  Protein-C will inactivate Factor VIII and Factor V, stopping the stair-step reaction from going through.
        
      • How do we dissolve this: so we have Plasminogen tries to change to Plasmin. Plasmin is going to destroy/break down Fibrin, and it will essentially lyse the clot. 
        
      • Plasminogen cannot change to Plasmin b/c there is an inhibitor enzyme that prevents this.  However, Protein-C says to that inhibitor to shut up.  We are inhibiting the inhibitor.
        
      • As soon as Protein-C says shut up, the clot will start to dissolve and Plasminogen will change to Plasmin.
        
        • There is an enzyme that is present all the time that converts Plasminogen to Plasmin.
          
      • Protein C inactivates the enzyme that inhibits Plasmin production – so more Plasmin will be produced and the clot breaks down.
        

         
         

• The Heart
  

   
   

  • Cardiac Muscle:
    
    • There is no neural stimulus for muscle contraction (neurons just regulate the muscles), instead the stimulus for contraction originates in the Pace Making Tissue
      
    • The SA node is Pace Making Tissue of the heart and it is known as the Pace Maker of the heart
      
    • Pace Making Tissue is Self-Depolarizing
      
    • There is a centralized pace maker and the excitation can then spread over the heart.
      
    • Resting = -60milivolts, Threshold = -40milivolts, Peak = about +10milivolts.
      
      • This represents an action potential in the SA node.
        
      • First we have the Depolarization action potential of Pace Making Tissue (Depolarization is due to Ca²⁺ NOT Na⁺)
        
      • We have Repolarization, which is due to the opening of the Potassium channels at the top, and it will go down to -60 mv, but there is NO Hyperpolarization (no going below the resting membrane potential) – but the K+ channels keep closing
        
      • Then the Potassium channels close, and the closing of the Potassium channels actually raises the action potential.
        
      • Starting at -60mv, at halfway up this action potential it will be up at about -50mv (since the threshold will be at -40mv), and at this point (the lower part of the rising action potential) we will have the opening of Calcium T-channels, which will raise the action potential up to -40mv, which in turn will fire another action potential due to the opening of the Calcium L-channels (this is the higher part of the action potential).
        
        • –50mv Calcium T channels opening (transient, not open very long)
          
        • –40mv Calcium L channels open (L=long)
          
      • Pre-Potential is the initial increase of the action potential, which is started by the over-closing of the Potassium channels, which in turn drives the Calcium T-channels to start opening. This causes a change in mv, and causes the Calcium L-channels to open allowing the action potential to peak.
        
      • The Calcium L channel closes and the whole process repeats, thereby causing beats.
        
      • Self-Stimulation is due to the SA node and the AV node. However, the AV node fires slower than the SA node, so the SA node is always considered the Pace Maker of the heart, and the AV node never gets a chance to complete this. The AV node fires due to the SA node firing.
        
        • If something happens to the SA node, the AV node can take over and function as a pacemaker for the heart.
          
      • Heart tissue contains Gap Junctions between cells so it can pass electrical activity from cell to cell – this is called Syncytial (excitation sweeps over the cell)
        
      • Only in the Ventricles, there is a conducting system called the Perkinje Fiber System, which is specialized tissue – it carries excitation to many parts of the Ventricles and tries to keep the synchronous contraction in the Ventricles. Makes for quick fast contractions throughout almost all of the Ventricles.
        
        • Recall: the Left ventricle is the big cup here, so the L and R have to be synchronous in order to function properly, and it can't be slowly sweeping over the surface
          
      • The Atria – it is slow contraction, which feeds into the ventricles, and has a sweeping action.
        
      • The ventricles have to pump all over the body so they must contract quickly (they can't sweet).
        

         
         

    • A typical Action Potential of a Ventricular Cell
      
      • Start at -90mv for resting membrane potential, and then the Sodium channels open (with other channels opening, but much slower than the Na channels)
        
      • Goes up and peaks at +20mv
        
      • Then the Sodium channels closes quickly at the top and the action potential starts to come back down and levels off at 0mv. This leveling off is due to the Calcium channels opening
        
      • Both T and L Calcium channel are open at this plateau stage, but L has the main effect because they stay open longer.
        
        • These channels let some sodium in, but they are more responsible for letting a lot more calcium in
          
        • The Calcium channels close and the Potassium channels take over the repolarization return the ventricular cell back down to the resting membrane potential of -90mv.
          
        • This process continues, but the process can be shortened depending on how fast your heart is beating.
          
        • The average heart rate is approximately 75 beats per min – the action potential lasts for 0.250 seconds
          
          
        • The action potential shortens to 0.150 seconds if your heart rate increases to 200 beats per minutes (this is the maximum pulse).
          
          • The faster your heart beats the short the action potential becomes
            
          • A long action potential means there is a long Absolute Refractory Period
            
      • Although the Sarcoplasmic reticulum is less extensive in cardiac muscle than it is in skeletal muscle, the cardiac muscle cannot pick up the calcium as quickly. But it is 3 times slower than skeletal muscle. Even though it is 3 times slower it can't be fired again and all the Ca will be going in before it gets a chance to fire again b/c the Absolute Refractory Period is too long.
        
      • The T-Tubule itself is 5 times the diameter of a T-Tubule in skeletal muscle (much larger in size)
        
      • The action potential comes across the surface of the cell and goes down to the T-Tubule where it is hitting a Calcium L channel there (just like in skeletal muscle). The Calcium L channel is going to allow the influx of Calcium thus hitting the Ryanodine receptors. The Calcium L channel is going to be sitting around Ryanodine receptors.
        
        • In the T-tubule the action potential runs into the Calcium L-channel. The Calcium-L Channel were called Dihydropyridine receptors in skeletal muscle b/c they 95% of them didn't allow any Calcium in at all and it was the physical motion that caused the opening of the Ryanodine receptors. But it is called a Calcium-L channel in cardiac muscle because there are no physical connections to the Ryanodine receptors and it does NOT have any Tetrads.
          
        • It is functioning solely as a Calcium L channel in cardiac muscle. There is only 1 Calcium channel for every 5 to 10 Ryanodine receptors and they are spread all over.
          
        • The Ryanodine receptors are all opened by Calcium influx, not by physical motion (like in skeletal muscle). There is NOT a physical connection to them like in skeletal muscle.
          
      • The calcium will stay out in the cytoplasm longer because the sarcoplasmic reticulum is less extensive – it stays out 45 miliseconds.
        
      • Once the heart beats it has to relax (it is impossible not to relax in between).
        
      • The excitation will sweep over the surface of the cell first, and then it will hit a T-Tubule and the T-Tubules are going to be similar
        
      • The Triads are the 2 Terminal Cisterns and a T-Tubule
        
      • WE have a similar set up in cardiac muscle, but the Triads are over the A-I junctions, so there are 2 Triads per sarcomere
        
      • In cardiac muscle the Triad sits over the Z-disk, so there is only 1 Triad per sarcomere
        
    • There is no way to have a sustained contraction in cardiac muscle, the calcium comes back in, the refractory period for the action potential is far longer than the amount of time that the calcium stays out there. This means that the muscle must contract.
      
    • The Contractile response of the heart begins at the peak of the action potential and lasts 1.2 times as long as the action potential.
      
    • Non-damaged Myocardium does not beat on it is own, it needs a Pacemaking tissue (like the SA node).
      
      • Damaged (cut into pieces) myocardium still beats when it is cut off from its nerve supply
        
    • Ringer's Lactated Solution – essentially IV fluid.
      
      • Sidney Ringer – cut frog hearts out. The beat of the heart was intrinsic and he wanted to know what was causing it to beat. The heart would sit on the table and still beat. It wasn't innervations that were causing it to beat and he found that if he passed distilled water through it he could actually make the heart beat longer.
        
      • He wrote a paper, but he had to take it out of the journal that it got published in when he found out that his lab tech was putting tap water into the hearts (he originally thought it was distilled water). So he went back and adjusted the ion concentration of the water, and he actually found out the he could keep a frog heart beating for up to a week all by just changing the fluid going through it.
        
      • If a patient comes in with unbalanced electrolytes or burns or something else, they are treated with this solution.