Flashcards in Ischaemia Deck (67):
How are glucose and amino acids moved across the blood brain barrier?
Carried mediated active transport
What is the circle of willis?
Structure in the brain where cerebral arteries meet
What is the purpose of the circle of willis?
Collateral circulation - all areas of the brain still perfused if one cerebral artery becomes blocked
Which cerebral artery is the most commonly occluded during strokes?
Middle cerebral artery
What happens in the hypoxia-inducible factor under normoxic conditions?
Cells continually produce HIF-1a and HIF-1b
In normoxic conditions, oxygen sensors detect oxygen
Prolyl Hydroxylase adds a hydroxyl group onto HIF-1a
Ubiquitin ligase adds a ubiquitin tail onto HIG-1a
HIF-1a is degraded by a proteasome
What happens in the hypoxia-inducible factor under hypoxic conditions?
HIF-1a forms a complex with HIF-1b called the HIF-1 transcription factor
HIF-1 translocates to the nucleus and transcribes genes for angiogenesis, glycolysis and cell proliferation such as VEGF and EPO
What is t-PA and what does it do?
Tissue plasminogen activator
Type of serine protease
Converts plasminogen into plasmin
Name two drugs that may be given as treatment to stroke patients
What is the name of the procedure during which a stent is inserted?
Percutaneous coronary intervention
or Coronary angioplasty
What kind of drug might a drug-eluting stent be coated in?
An immunosuppressant, that prevents smooth muscle cell proliferation by causing cell cycle arrest in G1/S phase
What are the steps of the extrinsic coagulation cascade?
Damaged cells release tissue factor
Trauma activates factor 7 --> 7a
Tissue factor and factor 7a form a complex in the presence of calcium ions and negative phospholipids
The complex activate factor 10 --> 10a
What are the steps of the intrinsic coagulation cascade?
Blood comes into contact with subendothelial cells
Kallikrein activates factor 12 --> 12a
Factor 12a activates factor 11 --> 11a
Factor 11a activate factor 9 --> 9a
Factor 9a joins with it's cofactor 8a
9a + 8a activates factor 10 --> 10a
Which clotting factor is also known as Hageman factor?
What is the common pathway of clot formation?
Factor 10a joins with it's cofactor 5a to form the prothrombinase complex
10a + 5a activates prothrombin --> thrombin
Thrombin activates fibrinogen --> fibrin
Fibrin forms a cross-linked mesh
Aggregates with platelets to form a clot
What are the four steps of atheroma formation?
Stable Plaque Formation
T cell activation
Ulceration and thrombus formation
Explain the step of endothelial dysfunction
Damage to the endothelium can occur from many causes
Monocytes adhere via VCAM-1 and migrate into tunica intima
Monocytes differentiate into macrophages
Macrophages phagocytose Oxidised or glycated LDL, forming fatty streaks made of foam cells
Explain the step of stable plaque formation
Smooth muscle cells migrate from the tunica media to tunica intima
They proliferate and act like myofibroblasts to produce collagen, which forms a fibrous cap, which can last many years with no symptoms
Explain the step of T cell activation
T helper cells 1 and 2 become recruited and activated
They release proinflammatory cytokines and cause foam cells to release MMPs
MMPs breakdown the fibrous cap so it becomes unstable...
Explain the step of ulceration and thrombus formation
As the MMPs breakdown the collagen, the damaged endothelium exposes/releases tissue factor, initiating the extrinsic coagulation cascade
A blood clot forms, breaks off and travels up to the brain...
What should blood pH be maintained at?
What 3 methods control blood pH?
Bicarbonate buffer system
Bicarbonate reabsorption in the kidney
Write out the bicarbonate buffer system equation
CO2 + H2O --> H2CO3 --> HCO3- + H+
If blood pH becomes too low, will breathing rate increase or decrease?
Low pH indicates lots of CO2
Breathing rate will increase to remove the CO2
If blood pH becomes too low, will there be more bicarbonate reabsorption or less?
There will be more bicarbonate ion reabsorption
Bicarbonate ions combine with H+
Shift the equation right
How is bicarbonate reabsorbed in the kidney?
H+/Na+ antiporters pump H+ into the lumen
H+ combines with the bicarbonate ions
Forms H2O and CO2
CO2 diffuses into cells as it is lipid soluble
Reforms bicarbonate in the cell
Where is the respiratory centre located?
Medulla oblongata and pons
What is the function of the respiratory centre?
Receives signals from central and peripheral chemoreceptors
Controls diaphragm and intercostal muscles
Increase/decrease breathing rate accordingly
Where are central chemoreceptors located and what do they detect?
On the ventral surface of the medulla oblongata
They detect the pH of CSF
Where are peripheral chemoreceptors located and what do they detect?
Carotid body and aortic arch
Detect concentrations of CO2 and O2 in the blood
How is excitotoxicity initiated?
Blood supply to a region of the brain becomes limited
Limited supply of oxygen (hypoxia)
Switched to anaerobic respiration
Less ATP produced
No ATP to power Na+/K+ pumps in membrane
Neuronal cell depolarises
Release of glutamate
What are the 6 mechanisms by which intracellular calcium concentration increases following glutamate release?
1. Glutamate activates AMPA and NMDA receptors leading to sodium and calcium influx
2. Sodium influx causes NCX sodium-calcium exchanger to reverse direction, starts bringing calcium in
3. Glutamate binds to mGlu group 1 receptors, causing release of Calcium from the ER
4. Calcium binds to RyR receptors, causing calcium induced calcium release
5. No ATP to power SERCA or PMCA
6. Intramitochondrial potential disrupted, releases calcium
Which g protein subunit are mGlu group 1 receptors coupled to?
How does calcium cause cell damage?
Calcium activates nNOS and caspases that damage cellular structures and initiates apoptosis
Mitochondria produce ROS
What is repurfusion injury?
Reintroduction of O2 causes surge in ROS generation
Electron transport chain restarts in mitochondria, forming ATP and ROS
ROS damage membrane structures, causing secondary wave of calcium influx
Proinflammatory cytokines also released
What does plasmin do?
Plasmin breaks down fibrinogen, fibrin and clotting factors 2, 5 and 8 into soluble products
Helps to breakdown clots
What does the PDK-1 gene code for?
Pyruvate dehydrogenase kinase
Inhibits pyruvate dehydrogenase, inhibiting conversion of pyruvate into acetyl coA
What is ischaemia?
Loss of blood flow to an organ
What are the symptoms of a blood clot located in one of the internal carotid arteries?
Numbness, weakness or paralysis on the opposite side of the body
What type of cells detect changes in oxygen concentration?
What is the acid and conjugate base in the blood buffer system?
Acid = carbonic acid, H2CO3
Conjugate base = bicarbonate ions, HCO3=
What is metabolic acidosis/alkalosis?
Change in blood pH that originate from kidney bicarbonate reabsorption. Caused by changes in bicarbonate ions
What is respiratory acidosis/alkalosis?
Change in blood pH that are respiratory in origin. Caused by changes in CO2
What are the levels of pH, CO2, HCO3-, and H+ ions during metabolic acidosis?
Where in the kidney is bicarbonate reabsorbed?
90 % in Proximal convoluted tubule
How does reabsorbed bicarbonate enter the capillary?
Na+/HCO3- cotransporter on the basolateral membrane
Where is the sample for arterial blood gas analysis usually taken from?
What 5 things are measured during arterial blood gas analysis?
What is base excess?
Excess bicarbonate ions in the blood
What is the sensitivity of a test?
Percentage of patients with the disease who will test positive
Higher chance of a false positive
What is a type 2 error?
Falsely accepting the null hypothesis
Saying there is no disease when there actually is
What is a type 1 error?
Falsely rejecting the null hypothesis
Saying there is disease when there is not
What is the specificity of a test?
Percentage of patients without the disease who will test negative
Higher chance of a false negative
Calculation for sensitivity?
True positives (True positives + False negatives)
Calculation for specificity?
True negatives (True negatives + False positives)
What is PPV and how is it calculated?
Positive predictive value
Proportion of positive results that are true positives
True positives/ (True positives + false positives)
What is NPV and how is it calculated?
Negative predictive value
Proportion of negative results that are true negatives
True negatives/(True negatives + False negatives)
Functions of the cerebellum
Damage results in?
Coordination of muscles
Damage causes tremors, inability to coordinate movement, difficulty performing rapidly alternating tasks
What is the ischaemic cascade?
Lack of ATP
No power for Na/K ATPase
Resting potential not maintained
High rise in intracellular calcium
Functions of the brain stem
Medulla oblongata - respiratory centre, controls breathing rate to maintain blood pH
What is excitotoxicity?
Over-activation of excitatory neurotransmitter receptors (NMDA and AMPA)
Leads to huge rise in intracellular calcium concentration
Production of ROS
Activation of caspases
Neuron damage and apoptosis
How many oxygen molecules can haemoglobin bind?
How is affinity of haemoglobin for oxygen affected by pH, and how does this help gas exchange in the lungs?
High pH = Higher affinity
Low pH = low affinity
Excess protons stabilise low affinity state
Also produce 2,3 BPG that stabilise low affinity state
At the lungs there is low CO2, so high pH, and higher affinity
2 things that affect haemoglobin affinity for oxygen
Positive cooperativity - once one oxygen molecule is bound, others are more likely to
What is atherosclerosis?
Thickening and hardening of the arterial wall due to build up of atheromas (plaques)
Causes artery to narrow
What are MMPs?
What is a zymogen?
Enzyme that needs to be broken down by another enzyme (proteolytic activity) to become active
Involved in blood clotting, as you don't want blood to clot unless the process is initiated