Physiology Review

Question 1

Describe the two types of diffusion and the factors that determine the rate of diffusion

Answer 1

1. Simple diffusion: * Movement through lipid bilayer if lipid soluble​​ * Movement through water channels if lipid insoluble * rate is determined by: * Amount of substance available * velocity of kinetic motion * number and size of openings in a membrane through which the molecules can move2. Facilitated diffusion * Requires a carrier protein * Requires a chemical binding process to move the molecules * May or may not move molecules against a concentration gradient * Requires additional energy over and above kinetic energy

Question 2

Describe how the protein channels can selectively allow passage of water and other substances

Answer 2

• Size of the channel pore * eg. aquaporin have a narrow channel that allows water molecules to pass in single file* The density of the channel proteins can alter the rate of diffusion* Channels can be selectively permeable allowing passage of only certain substances* Channels can be regulated by “gates” * voltage-gated channels will open with a certain electrical charge * Ligand-gated channels open with specific chemical binding

Question 3

Briefly describe facilitated diffusion.

Answer 3

• Facilitated diffusion requires a transmembrane carrier protein.* A substance can enter the protein that must bind to a specific binding site.* Binding to the binding site causes a conformational change in the carrier protein* The conformational change opens the opposide side.* Diffusion then occurs based on the diffusion gradient* Molecules can move either way through many carrier proteins

Question 4

Note two of the most important examples of facilitated diffusion within the body

Answer 4

1. Glucose * Via the family of GLUT proteins * GLUT-4 is activated (ligand-gated) by insulin * Facilitated diffusion of glucose through GLUT-4 can increase 10- to 20-fold in insulin sensitive tissues2. Amino acids

Question 5

What is active transport?Provide an example

Answer 5

• Active transport is the active movement of ions or substances across a cell membrane against a diffusion gradient.* The process of active transport requires cellular energy* Sodium and potassium are moved out of and into the cell respectively to help maintain a high intracellular potassium concentration and low intracellualr sodium concentration.* Calcium, hydrogen, iron, chloride, urate, sugars and most amino acids are also transported actively

Question 6

Briefly note the action of the sodium potassium pump

Answer 6

• 3 sodium and 2 potassium ion binding sites exist on the interior and exterior of the pump respectively* When 3Na+ and 2K+ ions are bound, the ATPase function is activated and ATP is cleaved to ADP, releasing energy* This energy release causes a conformational change are helps move the sodium out of the cell and the potassium inwards

Question 7

Describe the vital roles of the sodium and potassium pump with regards to cell homeostastis and function

Answer 7

• Ensures low sodium and high potassium within the intracellular fluid* Largely responsible for the total cell volume as water movement is linked strongly to sodium movement (via osmosis) * Activity of the pump is increased if there is evidence of cellular swelling* Ensures maintenance of an electrochemical gradient - negative within the intracellular space

Question 8

Describe the pumps responsible for maintaining intracellular cytosolic calcium at ~ 10,000 time less than the extracellular fluid

Answer 8

• Transmembrane calcium pump * Pumps cytosolic calcium out of the cell* Intracellular calcium pump * Pump calcium actively into intracytoplasmic vesicles within the sarcoplasmic reticulum or mitochondria* Both pumps have the same characteristics* The pump has specific binding sites for calcium and utilises ATPase for energy generation

Question 9

Briefly describe co-transportGive an example of a co-transport mechanism

Answer 9

• The concentration gradient of a molecule, primarily achieved via active transport provides a store of energy* The highly concentrated substance can move passively or via a carrier protein in the cell membrane* For certain carrier proteins, the highly concentrated substance together with a another “passenger” molecule must bind to activate the protein* The concentration gradient draws the substance along via simple diffusion while the passenger substance is pulled alongSodium-glucose cotransport - glucose is moved into the cell together with a single sodium ion.

Question 10

Describe the process of transport across cellular sheets.Where is this process most important

Answer 10

• Substances are generally absorbed via passive of facilitated diffusion at one side - often the luminal surface* Active transport occurs at the basal and lateral membranes* Active transport of sodium at the baso-lateral membranes also allows for osmosis of water - due to increased sodium concentration* Active transport helps to maintain the concentration gradient for diffusion at the luminal surfaceThis process occurs primarily within the GIT epithelium, gallbladder epithelium and within the renal tubular epithelium

Question 11

What is the resting membrane potential?How does the resting membrane potential originate?

Answer 11

• The resting membrane potential is the electrochemical gradient determined by the differential concentration gradients of charged particles across a membrane together with the permeability of the membrane to each of the ions* The sodium and potassium ratios between the intra- and extra-cellular fluid is as follows: * Potassium = 35 (140 mEq inside / 4 mEq outside) * Sodium = 0.1 (142 mEq outside / 14 mEq inside)* Potassium contribution to membrane potential is -94 mV* Sodium contribution to membrane potential is +61 mV * combined and based on the relative diffusion potential of potassium (100 x sodium), the overall membrane potential is -86 mV* Sodium potassium pump adds about -4 mV due to continual removal of +ve charge from the cell in Na+.* Note: The membrane potential of the various cell types varies immensely

Question 12

What is an action potential?

Answer 12

• An AP is a rapid change in membrane potential from negative to positive and an almost as rapid repolarisation back to negative. This change in membrane potential is transitory and propogating along a nerve cell fibre

Question 13

Describe the three stages of the action potential

Answer 13

1. Resting stage: * The nerve fibre is said to be “polarized” during this phase. * The resting nerve cell membrane potential is approximately -70 mV2. Depolarisation stage: * The membrane becomes suddenly permeable to sodium ions * Sodium ions rush into the cell * In large axons, large sodium inflows causes an overshoot to positive membrane potential * In smaller nerve cells the membrane potential approaches zero3. Repolarisation stage: * The sodium channels rapidly close * Potassium channels open to a greater degree than normal * Potassium rushes to the outside of the cell re-establishing the resting membrane potential

Question 14

Describe the 4 channels that are involved in the ion flows during propogation of an action potential

Answer 14

1. Voltage-gated sodium channel * activated as the resting membrane potential becomes less negative (ie. more positve) * Activated around -55 mV * Allows a rapid increase in sodium transport into the cell * The same voltage change that opens the activation gate also closes the inactivation gate. The inactivation gate closes more slowly than the activation gate * Inactivation gate usually remains closed until the resting membrane potential has again been reached2. Voltage-gated potassium channel * Open as the membrane potential becomes less negative * Slower to open than the sodium channels - open around the same time that the sodium channels are inactivated * Potassium outflow helps to restore the negative resting membrane potential3. NaK ATPase pump * Primarily for maintenance of the resting membrane potenital4. K+ Leak channel

Question 15

Briefly describe the role of calcium in the generation / propogation of the action potential

Answer 15

• Calcium pump and voltage-gated calcium channels help maintain very low calcium concentration within the cytosol* The calcium concentration is ~ 10,000-fold greater in the extra-cellular fluid * This creates a marked diffusion gradient and electrochemical driving force* The voltage-gated calcium channels open in response to an increasing membrane potential (or depolarisation) * They open 10-20 times slower than the sodium channels* As they are slow to open, they provide a more sustained depolarization, whereas the sodium channels play a key role in initiating action potential

Question 16

Describe the changes that lead to increased excitability of cell membranes when there is a calcium deficit

Answer 16

• A decrease in the interstitial calcium causes sodium channels to become more sensitive * Sodium channels will open when there is only a small increase in the resting membrane potential * Less calcium binding to the sodium channels likely affects the change in voltage required to open the gate* The increased sensitivity can eventually cause sodium channels to open spontaneously causing random AP generation* This increased excitability in peripheral motor nerves can lead to twitching and tetany

Question 17

Briefly describe the ionic changes that trigger generation of an action potential

Answer 17

• The AP is triggered when there is an increase in the resting membrane potential* The sodium inflow through the sodium channels needs to exceed the potassium lost via the slow potassium channels and overcome the changes due to the NaK pump.* As the sodium inflow exceeds the potassium outflow, the membrane potential increases. This leads to the positive feedback mechanism and initiation of an AP* An increase of 15-30 mV will trigger an AP

Question 18

Describe how a single action potential can propogate along the entire length of the axon / cell membrane

Answer 18

• The intial action potential involves a rapid inflow of sodium ions, increasing the local membrane potential.* The local increase is not isolated and will increase the adjacent membrane for 1-2 mm above threshold* The adjacent membrane crosses threshold and more sodium channels open* The sodium channels and thus the AP open rapidly along the entrie length of the cell membrane - axon in nerve cells

Question 19

What is myelin and how is it produced

Answer 19

• Myelin is produced by Schwann cells* Schwann cells envelop a nerve cell axon and rotate around it multiple times* During this process they lay down multiple layers of Schwann cell membrane * The membrane contains the lipid substance sphingomyelin

Question 20

How does myelin affect and influence nerve cell AP transmission

Answer 20

• Myelin is an excellent electrical insulator * Reduces ion flow through the membrane by 5000-fold* Small gaps are left in the myelin sheath adjacent each site of each Schwann cell * These gaps are called the *node of Ranvier** The electrical current is transferred between the nodes through both the intra- and extra-cellular fluid * This is referred to as saltatory conduction

Question 21

Discuss the benefits of conduction along myelinated nerves

Answer 21

• Depolarisation jumps from node to node * AP conduction velocity can be increased 5- to 50-fold* There is much less ionic transfer across the cell membrane * Much less energy is required to restore the ionic gradient across the cell membrane * Energy to restore the ionic gradient is primarily used by the NaK ATPase pump* As there is much reduced ionic transfer across the cell membrane, repolarisation can occur with little ionic transfer

Question 22

What are the major triggers that lead to generation of an action potential.Provide an example of each

Answer 22

Any trigger that causes sodium ion inflow can trigger an AP* Mechanical disturbance * Pressure sensation in the nerve endings within the skin* Chemical effect * Neurotransmitters within the brain* Passage of electrical impulse * Passage between adjacent or successive muscle cells in the heart or intestine

Question 23

Describe the general mechanism of muscle contraction

Answer 23

1. AP travels along a motor nerve terminating at a muscle fibre2. The nerve ending secretes a small amount of ACh3. ACh acts locally on the muscle cell membrane to open ACh-gated channels4. ACh-gated channels open allowing sodium inflow into the cell. This causes local depolarisation and opening of fast sodium channels - AP initiated on the muscle cell membrane5. AP travels along the muscle cell membrane6. The energy from the AP causes the release of calcium ions from the sarcoplasmic reticulum (via voltage-gated channels)7. Calcium ions initiate attractive forces between the actin and myosin filaments causing them to slide alongside each other8. After a fraction of a second the calcium ions are pumped back into the sarcoplasmic reticulum via a Ca²⁺ pump9. Calcium removal causes the muscle cell contraction to stop.

Question 24

Describe the three sources of enegy that are utilised for muscle contraction.Note that the energy is provided in the form of ATP

Answer 24

• Energy is utilised by the myosin myofilament for the “walk-along” mechanism than enables muscle contraction* Energy is also utilised to restore calcium concentrations (calcium pumps) and both sodium and potassium concentrations.1. Phosphocreatine * Contains a high energy phosphate bond that is cleaved to convert ADP to ATP2. Glycolysis * anaerobic process that involves the breakdown of glycogen into glucose and subsequently into pyruvate and lactic acid. * Liberates energy that converts ADP to ATP and helps restore phosphocreatine levels * ATP regeneration is ~2.5 x faster than from aerobic metabolism3. Oxidative metabolism * Involves the combining of oxygen with the end products of glycolysis and other food stuffs in the cells to form ATP * Can utilise fatty acids and fats and carbohydrates

Question 25

Describe the characteristics of slow muscle fibres

Answer 25

• Smaller than large fibes* Innervated by smaller neurons* More extensive blood vessel network for provision of oxygen* Increased mitochondria when compared to large fibres* Large volumes of myoglobin * Myoglobin binds oxygen to store it for use on demand

Question 26

Describe the characteristics of fast muscle fibres

Answer 26

• Large than slow fibres for increased force of contraction* Extensive sarcoplasmic reticulum for calcium storage * Provides a sotre for rapid calcium release during contraction* Large amount of glycolytic enzymes* Less extensive vascular supply* Fewer mitochondria when compared to slow fibres* Less myoglobin than slow fibres

Question 27

Describe the important neurological aspects of the maintenance of normal skeletal muscle tone

Answer 27

• Even at rest, there is a degree of muscle taughtness or tone* As muscle contraction of any sort requires an action potential, muscle tone is initiated by a low rate of small nerve impulses coming from the spinal cord* The spinal nerve impulses are in part controlled by the CNS and partly controlled by the signals that originate in the muscle spindles

Question 28

Briefly describe the cellular process that lead to muscle fatigue

Answer 28

• Fatigue results from the inability of the contractile elements and the underlying metabolic processes to continue to supply an appropriate work output* The degree of fatigue increases in almost direct proportion to depletion of glycogen stores within the muscles* Prolonged intense activity can also lead to mild diminishing of nerve output and reduced AP generation* Interruption of blood flow and thus oxygen through a contracting muscle will lead to fatigue rapidly (within 1-2 minutes)

Question 29

Describe the major components of the neuromuscular junction

Answer 29

• Terminal portion of a large myelinated nerve fibre * Branches to supply 3-100’s of individual muscle fibres * Contains large numbers of mitochondria to synthesis ATP - the energy source for ACh synthesis * Contains vast numbers of synaptic vesicles containing acetylcholine* The nerve ending sits within a synaptic trough of the corresponding muscle cell * There are numerous invaginations or folds of the muscle cell membrane to greatly increase surface area * These folds are called subneural clefts* The synaptic cleft/space is ~20-30 nm wide* Acetylcholine esterase is present in large quantities in the synaptic cleft

Question 30

Describe the process by which acetylcholine is released from a pre-synaptic nerve terminal

Answer 30

• AP spreads down the nerve to the terminal* AP stimulates the opening of voltage gated calcium channels* Calcium diffuses into the axon cytoplasm* A calcium dpendent protein cascade occurs * Vesicles are released from the cytoskeleton * Vesicles move to the active zone adjacent the nerve terminal * Eventually, the ACh vesicles anchor to the pre-synaptic cell membrane* Docking of the vesicles leads to fusion of the vesicular membrane with the cell membrane and release of ACH into the synaptic cleft

Question 31

Briefly describe the interaction between acetylcholine and the acetylcholine receptor together with the down stream effects

Answer 31

• ACh is released into the synaptic cleft after nerve stimulation by an action potential* The ACh diffuses across the synaptic space with 2 ACh molecules required to bind to the ACh receptor for activation * The ACh receptor is composed of 5 protein subunits that essentially form a tube. * Binding of ACh to the two alpha subunits causes a conformational change* Sodium ions are allowed to passage the ACh receptor once it has been activated* Sodium entry into the cell increases the membrane potential and activates fast sodium channels* This ensure propogation of the AP along the muscle cell membrane

Question 32

Describe the various drugs or processes that can alter the function of the neuromuscular junction

Answer 32

1. Stimulants * Nicotine, carbachol, metacholine can all act on the AChR similarly to ACh itself * These substances are often not broken down by ACh esterase * Can have a prolonged activity causes repeated muscle stimulation / AP generation2. Stimulants that act by inactivation of AChE * Neostigmine, physostigmine, pyridostigmine * Most of the drugs bind and inactivate AChE for several hours * Diisopropyl fluorophosphate - nerve gas agent - dines to AChE for several weeks3. Blocking agents * Curariform drugs * Block the action of ACh on the receptor * Botulinum toxin * Blocks the release of ACh from the presynaptic nerve terminal4. Immune disease * Myasthenia gravis * Antibodies attach to an inactivate / destroy the acetylcholine receptor on the post-synaptic membrane

Question 33

Describe the movement of calcium ions into and out of the sacoplasmic reticulum during muscle contraction

Answer 33

• Calcium ions are stored in abundance within vesicles in the sarcoplasmic reticulum* ACh binding to the AChR allows Na+ inflow - this opens Na+ channels and initiates an AP in the muscle membrane* The AP propogates along the muscle cell membrane and the T-tubules* Voltage-gated ryanodine receptor channels activate the calcium release channels in the membrane of the sarcoplasmic reticulum* Vesicles bind to the SR and release calcium via exocytosis into the sarcoplasm for use in myofibre contraction.* The sarcoplasmic reticulum Ca²⁺ATPase pump removes calcium from the sarcoplasm - pumps back into the SR * Additionally, Calsequestrin can bind up to 40 calciumn ions within the SR

Question 34

Briefly describe the suspected pathophysiology of malignant hyperthermia

Answer 34

• Genetic mutations in the ryanodine receptor gene have been identified in humans with malignant hyperthermia * Similar defects have been noted in dogs, however malignant hyperthermia can occur despite the presence of a normal ryanodine receptor gene* MH leads to unregulated passage of calcium ions into the sarcoplasm from the SR.* Increased calcium within the sarcoplasm leads to uncontrolled muscle fibre contraction * Sustained skeletal muscle contractions * Heat generation due to the large muscle volume in the body * Cellular acidosis due to rapid production of lactic acid* With severe cases, the muscle cells can breakdown and release potassium and muscle cell enzymes (CK being the obvious one) and myoglobin

Question 35

List the classical clinical signs associated with malignant hyperthermia

Answer 35

• Hyperthermia* Tachycardia* Tachypnea* Increased carbon dioxide production* Increased oxygen consumption* Acidosis* Hyperkalaemia* Muscle rigidity and rhabdomyolysisAll clinical signs are associated with a hyper-metabolic stateOften induced by exposure to the volatile anaesthetic agents or with excessive exercise in some dog breeds

Question 36

Describe the treatment recommendations for malignant hyperthermia

Answer 36

• Active cooling* Fluid support * Cooled fluids * Close monitoring of serum potassium levels * Increase GFR to manage pigmenturia and potential renal damage* Dantrolene * Antagonises the ryanodine receptors * Inhibits release of calcium from the sarcoplasmic reticulum and can blunt the underlying process

Question 37

Note the major anatomical similarities and differences between smooth and skeletal muscle

Answer 37

• Smooth muscle are tiny in comparison with skeletal muscle fibes up to 30 times as wide and hundreds of times longer* Smooth muscle does not contain the troponin complex that is necessary for control of skeletal muscle contraction* Both utilise sliding actin and myosin myofibrils * Both sets of myofibres respond and contract in response to calcium release from the SR * Both sets of muscle cells are essentially innervated by a single neuron

Question 38

Describe the 5 ways in which the various types of smooth muscle are distinctive

Answer 38

1. Physical dimensions2. Organisation into bundles or sheets3. Response to different types of stimuli4. Characteristics of innervation5. Function

Question 39

What are the characteristics of multi-unit smooth muscle?

Answer 39

• Each fibre operates independently and is often innervated by a single nerve ending* Outer layer is covered with a glycoprotein and fine collagen mixture that helps insulate each fibre from those adjacent* Each fibre can contract independently* Controlled by nerve signalsExamples:* Ciliary muscle of the eye* Iris muscle of the eye* Piloerector muscles that cause erection of the hairs

Question 40

What are the major characteristics of unitary smooth muscleProvide examples of unitary smooth muscle

Answer 40

• Also called syncytial muscle or visceral smooth muscle** Masses of hundreds of muscle fibres contract together as a single unit Arranged in sheets or bundles* Cell membranes are adherent to adjacent cells * Contractile force can be transmitted to the adjacent cell* Cells are joined by gap junctions * ​Ions can travel freely between cells triggering contraction without an AP * AP can travel between cells also* All above leads to synchronized contractionExamples:Visceral organs - gastrointestinal tract, urinary tract, bile ductsMany blood vessels

Question 41

Describe the structures of smooth muscle as they relate to contractile ability

Answer 41

• Multiple dense bodies througout the cell * Some are attached to the cell membrane * Intercellular bonding proteins link dense bodies from adjacent cells* Large numbers of actin filaments extend from the dense bodies* A single myosin filament lies centrally between two dense bodies* The myosin filament has side-polar cross bridges * The opposite sides hinge in the opposite direction * The smooth muscle cell can contract as much as 80% of their length (30% for skeletal muscle)

Question 42

Describe the contrasting characteristics of smooth versus skeletal muscle contraction at a cellular level

Answer 42

• Myosin cross bridge cycling in smooth muscle is slow, skeletal muscle is rapid* Less ATPase activity in the myosin head likely contributes due to slower ATP degradation * ATP cycling fuels the attachment and release of the myosin cross bridges and head movement* Low energy utilisation during smooth muscle contraction primarily due to reduced ATP cycling* Smooth muscle is slow to start contracting and contraction lasts much longer ~ 30 times as long* Increased force of contraction in smooth muscle due to prolonged attachment of the myosin cross-bridge* “Latch mechanism” allows for prolonged maximal smooth muscle contraction with little energy expenditure* Stress-relaxation of smooth muscle allows many hollow visceral organs to essentially maintain a stable/steady intra-luminal pressure despite large volume fluctation

Question 43

Describe the role of calcium and calmodulin in smooth muscle contraction

Answer 43

• Calcium is allowed into the cell from the extracellular fluid (and released from the SR) after AP propogation due to activation of voltage gated calcium channels* Calcium ions bind reversibly with calmodulin* Calcium-calmodulin activates the myosin light chain kinase* The myosin light chain becomes phosphorylated* Once phosphorylated, the myosin head can bind repeatedly with the actin filament and hinge * This binding occurs in the presence of ATP

Question 44

Describe the way calcium is modulated and altered and the effect on smooth muscle contraction

Answer 44

• Poorly developed sarcoplasmic reticulim * The majority of calcium originates from the extracellular fluid * Trasport of extracellular calcium is slow when compared to release from the SR* Force of contraction of smooth muscle is highly dependent on the extracellular calcium concentration * This is not the case for skeletal muscle due to large calcium storage within the SR* An ATP dependent calcium pump removes excess calcium * This pump is much slower than the SR calcium pump * Prolonged and slow contraction* Myosin phosphatase is required to split the phospahte from the myosin regulatory light chain * This process stops the cycling process and terminates contraction

Question 45

Describe the various stimuli that elicit an AP in smooth muscle

Answer 45

• Electrical impulse - from neurons* Chemical message * Hormones* Stretch receptors* Spontaneous generation within the fibre itself

Question 46

Describe how and why smooth muscle can produce an action potential with a plateau

Answer 46

• The plateau phase of the smooth muscle action potential allows for a prolonged force of contraction * Useful in the uterus, ureter and within certain types of vascular smooth muscle* Smooth muscle has few voltage-gated sodium channels* Calcium flow to the interior of the cell is responsible for the propogation of the smooth muscle AP* Calcium channels open far slower than sodium channels* Calcium channels remain open for a prolonged period of time* Calcium acts to propogate the AP and also work on contractile elecments

Question 47

Describe the slow wave potential present in numerous smooth musclesWhy is the slow wave potential important?

Answer 47

• The slow wave potential is a local property of the smooth muscle cell membrane* There is a rhythmic change in the membrane potential* Specific cause for the slow wave is unknown * Changes in ion transport outward through the membrane (likely Na⁺ pumping) * Rhythmic change in conductance of the ion channels* When they are “strong” enough they can elicit an AP and therefore smooth muscle contraction* This “pacemaker” potential is important for the rhythmic contractions of the gut

Question 48

Describe the various local control signals for smooth muscle contraction, giving examples.

Answer 48

• The smooth muscle of arterioles, meta-arterioles and pre-capilliary sphincters have little to no nervous supply* In the normal resting state, these vessels remain contracted to preserve blood pressure* These vessels can relax in certain circumstances to allow increased blood flow: * lack of local tissue oxygen concentration * Excessive carbon dioxide * Increased hydrogen ion concentration * Adenosine * Lactic acid * Increase potassium * Nitric oxide * Increased body temperature

Question 49

List the various hormones that can have an effect of smooth muscle tone

Answer 49

• Epinephrine* Norepinephrine* Angiotensin* Endothelin* Vasopressin (ADH)* Histamine* Oxytocin* Serotonin

Question 50

Describe the mechanisms by which the excitability of smooth muscle can be increased or decreased by the effect of hormones.

Answer 50

• Various hormones bind to receptors that will then directly impact the state of either sodium or calcium channels​Excitation* The net result can be depolarisation, generation of an AP or enhancement of already present APs* Hormone may stimulate internal changes within the cell that trigger release of calcium from SR - contraction without an AP_Inhibition_* Hormone may initiate closure of the sodium or calcium channel* May increase opening of the potassium channels - increase potassium leak decreases the membrane potential * Can trigger hyperpolarisation which strongly inhibits muscle contraction* May activate production of intracellular cAMP or cGMP (messenger proteins) * These can alter the phosphorylation of various enzymes thereby altering contraction * Increased activity of the calcium pumps on both the SR and cell membrane –> reduce cytosol calcium and therby contaction

Question 51

Briefly describe the actions and interactions of the two major smooth muscle neurotransmitters

Answer 51

1. Acetylcholine2. Noradrenaline* Both are secreted by neurons but not the same neuron* Both neurotransmitters can trigger either excitation or inhibition depending on the receptor types on the surface of the smooth muscle* When acetylchoine is excitatory, noradrenaline is typically inhibitory, and vise versa* The interplay between these two neurotransmitters is essential for normal function of the autonomic nervous system and maintenance of appropriate smooth muscle tone

Question 52

Describe the three basic principles that underlie circulatory function

Answer 52

1. Blood flow to tissues is controlled according to the tissue needs * Increased activity - increased O2 utilisation and waste build up - increased blood flow * It is not possible for nutrient supply to be increased sufficiently at a local level by a global mechanism2. Cardiac output is the sum of all local tissue flows * All blood that flows through the tissues is returned to the heart via the veins - and immediately pumped back into the arteries * Nerve signals are required to assist in this regulation3. Arterial pressure is generally regulated independent of either local flow or cardiac output * Increased heart rate or force of contraction * Increased venous tone for return of blood from the storage pool * Generalised increase in arteriolar resistance increases pressure in the great arteries * Renal / hormonal control occurs more slowly - hours and days

Question 53

Describe the relationship between vascular pressure and distensibilityHow does this relationship affect the arterial pressure in the systemic versus pulmonary circulation

Answer 53

• The vascular walls thickness is directly linked to the pressure the particular vessel needs to accomodate* The distensibility of the vessels in inversely proportional to the typical pressure transmitted through the particular vessel * The distensibility of the systemic arteries is lowest * The distensibility of the venous system is significantly greater that the veins* The pulmonary arterial pressure is normal ~ 20-25 mmHg or about 1/6 that of the systemic arteries * Therefore the distensibility of the pulmonary arteries is about 6 times greater than the systemic arteries

Question 54

Describe vascular compliance and the relationship between compliance and vascular distensibility

Answer 54

• Vascular compliance or capacitance refers to the volume of blood that is able to be stored in a respective vascular bed at a given pressure* Vascular compliance is achieved by the sum of vascular distensibility multiplied by volume* Therefore: systemic vein is ~ 8x more distensible and has a volume ~ 3x more than corresponding artery * Vascular compliance of the vein is ~ 24 times that of the artery

Question 55

Describe the effect on the arterial and venous systems with both sympathetic stimulation and inhibition

Answer 55

• Arterial system * Low compliance system * Reduced volume causes pressure to drop rapidly * Increased and decreased sympathetic tone will alter the vascular diameter and therefore total blood flow * This can be utilised to direct or shunt blood to or away from a vascular bed* Venous system * Increased tone will reduce capacitance in the high compliance system * Increased tone can markedly increase blood return to the heart * Especially important during haemorrhage to maintain systemic arterial blood pressureOverall, an increase in vascular tone will increase the volume of blood returned to the heart and therefore cardiac output

Question 56

Describe delayed- and reverse delayed-compliance

Answer 56

• A sudden increase in blood volume causes an acute increase in blood pressure* Over a period of minutes, stress relaxtion occurs * Stress relation leads to stretching or relaxation of the smooth muscle cells and they extend to longer lengths* The stress relaxation leads to an increased vascular volume and reduction in the local blood pressure* Reverse delayed-compliance works in the opposite direction when there is a sudden drop in blood pressure. * Reduced trigger for smooth muscle stretch and the smooth muscle fibres contract

Question 57

How does arterial distensibility affect tissue blood flow. Describe the differences in blood flow if the arteries were poorly distensible

Answer 57

• Distnesibility of the arterial network essentially smooths out the sytolic movement of blood* If the artery was poorly distensible, all blood moved from the heart during systole would need to move at the same rate through the peripheral circulation * Duing diastole there would be essentially no movement of blood* The distensibility allows for relaxation / stretch during systole and a rebound during diastole * The net effect is a reduction in the pulsatile movement of the blood from the heart by the time the peripheral vascular beds are reached

Question 58

Describe the process by which an automated oscillometric blood pressure machine can determine systolic, mean and diastolic blood pressure

Answer 58

• An appropriately sized cuff is applied to a limb (overlying an artery)* The cuff is slowly inflated until changes in the blood pressure cuff caused by arterial flow ceases* The cuff pressure is slowly reduced until blood first flows through the underlying artery. This is detected by subtle changes in the cuff pressure and represents systolic arterial pressure* As the cuff pressure reduces, the change in pressure due to blood flow increases. The maximal change in pressure caused by arterial flow represents the mean blood pressure* When the change in blood flow (and therefore cuff pressure) reduces to zero, this represents the diastolic pressure

Question 59

Describe the relationship between central venous pressure and the function of the right heart

Answer 59

• Central venous pressure is equivalent to the pressure within the right atrium* CVP is regulated by * the ability of the right heart to pump blood to the lungs * The tendency of blood to flow from the peripheral vein back into the right atrium* If the heart is pumping strongly, there is reduced pressure within the right atrium as blood is moved to the ventricle and out to the lungs* If there is weakness in the right heart contraction, then less blood is moved forward and CVP rises

Question 60

Describe the peripheral venous circulation factors that can lead to an increase in CVP

Answer 60

• Increased blood volume will lead to an increase in peripheral venous pressures * This is transmitted to the right heart with resultant increase in CVP if the right heart does not increase output accordingly* Increased large vessel tone will increase peripheral vascular pressures and CVP* Arteriolar dilatation will lead to reduced arteriolar resistance and increased blood flow into the venous system. This increased pressure in the venous system can lead to an increased CVP

Question 61

Describe the branching and anatomical structures from arteries to the level of the capilliary

Answer 61

• large arteries have highly muscular walls* These branch to provide specific nutrient arteries to each organ* Nutrient arteries branch up to 6-8 times before they are called arterioles* Arterioles branch a further 2-5 times to form the metarteriole * Arterioles are highly muscular and can vary size by many times * The small arterioles control the blood flow to a particular tissue bed * The local tissue environment in turn controls the diameter of the arteriole* Metarterioles have a discontinuous muscular wall* A smooth muscle fibre encircles the metarteriole at the entry to the capilliary * This pre-capillary sphincter can open or close the capillary

Question 62

The various tissues have different capillary wall structure to help serve different purposes.Explain the different capillary structures in the brain, liver, GIT and kidney and the purpose for the differences

Answer 62

The major structural difference between the various organ capillaries relates to how molecules move through the capillary wall and the underlying function of the organ1. Brain: capillary endothelial cells are mainly held together by tight junctions * Minimal diffusion across the wall. Tiny molecules that can dissolve in the membrane will pass readily including water, oxygen and carbon dioxide2. Liver: The endothelial intercellular cleft is almost wide open such that almost all plasma substances including the proteins can diffuse into the tissues3. GIT: Pores are midway between the liver (open) and muscle (tight)4. Kidney: Specialised small oval windows (fenestrae) penetrate through the middle of the endothelial cells. Large volumes of small molecules can pass without having to traverse the intercellular clefts

Question 63

Describe the forces that ensure appropriate movement of fluid between the capillary and the interstitial space

Answer 63

• Capillary hydrostatic pressure * Forces fluid out of the capillary* Interstitial fluid hydrostatic pressure * Resists fluid movement out of the capillary * or forces fluid back into the capillary* Plasma oncotic pressure * Provides an osmotic pressure gradient for the movement of water into the capillary* Interstitial fluid oncotic pressure * Tends to cause osmosis of fluid out of the capillary network

Question 64

Describe the anatomy of the terminal lymphatic capillaries and the special function that this anatomy allows

Answer 64

• The endothelial cells of the lymphatic capillaries are attached by anchoring filaments to the adjacent interstitial tissue* There is a small overlap of the adjacent endothelial cells that results in a valve like structure* Interstial fluid and suspended particles can “push” the valve open * Negative pressure within the lymphatics enables the valve to open* The valve works to prevent backflow of fluid leaking from the vessel* This structre allows passage of large proteins and suspended particles to flow out of the interstitial space and eventually back into the blood stream

Question 65

Describe the formation of lymph and relative components in the periphery and contrast with the thoracic duct

Answer 65

• Lymph is essentially derived from the flow of interstitial fluid * Lymph in the terminal lymphatic capillaries is essentially equivalent to the composition of the interstitial fluid * Protein content of ~ 20 g/L* Lymph formed in the liver has a protein content of ~ 60 g/L as the hepatic capillaries are significantly more permeable* The gut lymphatics absorb fluid with ~ 40g/L protein* ~2/3 of all lymph is formed within the gut and liver * In the thoracic duct, the lymphatic fluid can have a protein content of 30-50 g/L* Gastrointestinal lymphatics are also responsible for the absorption of lipids from food * Thoracic duct lymph can be 1-2% fat after a fatty meal* Large particles including bacteria can enter the lymp * These particles are generally removed and destroyed as the lymph passes through the lymph nodes

Question 66

Describe the various mechanisms that contribute to the normal flow of lymphatic fluid

Answer 66

Internal / intrinsic lymph movement* Lymphatic valves prevent lymph back flow* The segments of lymphatic vessels between valves function as separate automatic pumps * As a segment fills, contraction occurs moving fluid through the next set of valvesExternal intermittent compression of lymphatics* Contraction of surrounding skeletal muscle * Lymph flow can increase by 10-30 times during periods of exercise* Movement of body parts* Pulsations of arteries adjacent the lymphatics* Compression of tissues by objects outside of the body

Question 67

Briefly describe the two major theories that best explain the regulation of local blood flow

Answer 67

1. Vasodilator theory * Increased oxygen utilisation leads to formation of vasodilatory substances * adenosine, carbon dioxide, adenosine phosphate compounds, histamine, potasium ions, hydrogen ions * Increased vasodilatory substances increases vascular diameter and blood flow * Increased blood flow helps return the concentration of these substances towards normal2. Oxygen demand theory * Oxygen is required for smooth muscle contraction * In the absence of oxygen, vascular smooth muscle cells relax and the vessels dilate * Eg. reduced oxygen within the capilliary could lead to relaxation of the pre-capillary sphincter * Conversely, the pre-capillary sphincters would contract more strongly in the presence of oxygen, reducing blood flow.

Question 68

Describe the two proposed theories that explain why blood flow drops towards normal after a sudden rise in blood pressure

Answer 68

• An initial sudden rise in arterial blood pressure causes an acute increase in blood flow in the arterioles and capillaries_Metabolic Theory: (likely the dominant process)* Increased blood flow provides increased oxygen to the local tissue bed.* Increased blood flow washes away waste products and vasoactive substances including H+ ions, potassium and carbon dioxide - all of which can trigger vasodilation* The net effect is increase oxygen and reduced vasodilators * Vasoconstriction ensues_Myogenic theory:* Increased arterial pressure causes increased vascular smooth muscle stretch* Increased stretch triggers reactive vascular constriction * Initiated by stretch-induced vascular depolarisation * depolarisation opens voltage gated calcium channels * Calcium ion influx activates the contractile myofibrilar network* Other pressure related changes to vascular ion channels or extracellular proteins tethered to cytoskeletal elements

Question 69

Describe the special mechanism of tubuloglomerular feedback as it operates within the kidney

Answer 69

• The composition of the tubular fluid in the early distal tubule is detected by the macula densa * The macula densa is a group of specialised epithelial cells located at the junction between the ascending loop of Henle and the distal convoluted tubule* This area is referred to as the juxtaglomerular apparatus and includes the MD and both afferent and efferent arterioles* Feedback from the MD can lead to constriction or dilatation of the afferent arteriole to decrease or increase blood flow respectively * This constriction occurs via the release of ATP from the MD cells - converted to adenosine (constrictor)* Increased NaCl at the MD signals a high GFR while a low NaCL concentration at the MD suggests low GFR

Question 70

What two triggers other than oxygen concentration can significantly alter blood flow within the brain

Answer 70

• An increase in either the concentration of hydrogen ions or carbon dioxide causes significant vasodilation* Increased concentrations of either causes vasodilation and increased blood flow to rapidly wash out excessive CO2 or H⁺* This is important as the level of excitability of the brain is highly dependent on the concentration of CO2 and H⁺

Question 71

Describe the special mechanisms that can alter cutaneous and subcutaneous blood flow

Answer 71

• Cutaneous blood flow is largely controlled by the sympathetic central nervous system (medullary raphe in the lower brain stem)* Large changes in the volume of blood flow to the skin can occur with temperature changes* With high temperatures, cutaneous blood flow can more than double* With low temperatures, cutaneous blood flow can reduce to just above zero (while still providing enough to meet the metabolic demands)

Question 72

Describe the metabolism and action of nitric oxide

Answer 72

• Produced in the endothelial cells * Endothelial derived nitric oxide synthase synthesise NO from oxygen, arginine and inorganic nitrates* NO diffuses out of the endothelial cell with a half life of ~6 seconds* Activates suluble gyanylate cyclases in vascular smooth muscle * converts cyclic guanosine triphosphate to guanosine monophosphate (cGMP)* cGMP activates a cGMP dependent *protein kinase** Smooth muscle cells relax

Question 73

What are the triggers for nitric oxide release

Answer 73

• Increased sheer stress on the endothelial surface * Due to viscous drag of the blood * Increased blood flow through the microvasculature secondarily triggers NO release from the larger arterioles* Angiotensin II * Protection mechanism against excessive vasoconstriction* Other vasoconstrictors

Question 74

Describe the metabolism and action of endothelin

Answer 74

• Produced and stored within vascular endothelial cells * Levels increase when the endothelium is injured* Damage to the endothelium is the most common stimulus for release* Endothelin is a potent vasoconstrictor * Can help constrict arteries as large as 5 mm in diameter* Endothelin can be upregulated by chronic hypertensin induced vascular damage

Question 75

Briefly discuss the mechanism for adaptation to chronic changes in local blood flow.Comment on both new growing tissue and established or older tissue

Answer 75

• Vascular remodelling within newly growing tissue is quite rapid* The vascular channels change and adapt to the underlying requirements of the tissues * ie. Vascularity adapts to the underlying metabolic demands of the tissue* Vascular remodelling can permanently alter blood flow to a tissue after chronic increases due to conditions such as hypertension. * Note this occurs as acute alterations fail to return blood flow 100% to normal.* Older tissues with established vascularity may adapt less readily* Neoplastic tissue (new growth) can have extensive vascular growth and remodelling

Question 76

Note the 4 best described vascular growth factorsNote the pathway for release of these factors

Answer 76

• Vascular endothelial growth factor (VEGF)* Fibroblast growth factor* Platelet derived growth factor (PDGF)* Angiogenin* Deficiency of tissue oxygen* Release of hypoxia inducible factors (HIFs)** HIFs work as transcription factors Upregulate the genetic expression and the formation of the vascular growth factors

Question 77

Briefly describe the process of angiogenesis in response to a vascular growth factor

Answer 77

• The endothelial basement membrane dissolves* Rapid division of the endothelial cells occurs* New endothelial cells grow out in a cord like structure towards the vascular growth factor (hypoxic tissue)* The endothelial cells fold over each other to form a tube* Two growing tubes of cells join to form a new blood vessel* If there if large enough flow in the new vessel, then smooth muscle cells will invade the wall* Arterioles, venules and even larger vessels can form this way

Question 78

List the 4 most important vasoconstrictors

Answer 78

• Norepinephrine* Epinephrine* Vasopressin (ADH)* Angiotensin II

Question 79

Briefly describe the dual action effect of NE and Epinephrine on vascular tone

Answer 79

• NE is a potent vasoconstrictor* Epi is generally a vasoconstrictor, less effective than NE * Epi can cause vasodilation in certain circumstances * Eg. coronary vessels during exercise* Sympathetic nervous stimulation * NE is released as the neurotransmitter * Excites the heart, constricts the veins and arterioles * Stimulates the adrenal medulla * NE and Epi are secreted into the blood* Direct nerve stimulation and indirect effectsa s a hormone entering the blood stream

Question 80

Briefly describe the metabolism and role of bradykinin in vascular tone

Answer 80

• Bradykinin is a potent vasodilator * Causes potent arteriolar dilatation * Causes increased capillary permeability* A proteolytic enzyme kallikrien is present in the blood and tissue fluids in an inactive form* maceration of the tissue or blood and tissue inflammation activate kallikrein* kallikrein acts on alpha2-globulin to release kallidin** Kallidinis converted by tissue enzymes to bradykinin** *Bradykinin is rapidly inactivated by ACE and carboxypeptidase Kallikrein inhibitor rapidly breaks down kallikrein

Question 81

Briefly detail the effect of the various ions/chemicals on the local vascular tone

Answer 81

1. Calcium * Increased intracellular calcium - vasoconstriction2. Potassium * Increased intracellular potassium - vasodilatation or inhibition of vasoconstriction3. Hydrogen ions * Increases - arteriolar dilatation * Decreases - arteriolar constriction4. Magnesium * Increases inhibit smooth muscle contraction * Powerful vasodilation5. Anions - acetate and citrate * Mild degrees of vasodilation6. Carbon dioxide * moderate vasodilation widespread * marked vasodilatation within the brain * CO2 acting on the vasomotor centre in the brain stimulates the sympathetic nervous system * This leads to widespread vasoconstriction

Question 82

Describe the three major changes that occur when the sympathetic nervous system is triggered and the net end effects, with regards to blood pressure and vascular tone

Answer 82

1. Arteriolar constriction * increased total peripheral resistance and increase in mean arterial blood pressure2. Veins are strongly constricted * Increases the effective circulating volume by reducing the volume in the peripheral storage pool * Increased cardiac return leads to increased cardiac output3. Direct stimulation of the heart * Increases in both rate and force of contraction * Increased cardiac output

Question 83

List the various reflexes that work to maintain normal arterial blood pressure

Answer 83

1. Baroreceptor reflex2. Carotid and aortic chemoreceptors3. Atrial and pulmonary artery reflexes4. Atrial reflexes - The volume reflex

Question 84

Briefly describe the baroreceptor reflex and how it helps to regulate arterial blood pressure.

Answer 84

• This is essentially a series of stretch receptors located in the walls of the large systemic arteries * The aortic arch and carotid arteries are most well described* A rise in arterial pressure causes stretch in the baroreceptor wall* Stretch triggers an increase in signals to the vasomotor region in the CNS * The signals are greatest when there is a rapid change in arterial pressure* Feedback signals are delivered via the autonomic nervous system * To reduce arterial pressure towards normal * Vasoconstrictor region is inhibited * Vasodilator region or vagal parasympathetic centre is excited* The overall function of the baroreceptor reflex is to minimise the minute by minute variations that would be seen in arterial blood pressure due to day to day activites

Question 85

Briefly describe the chemoreceptors and how they exert their effect on arterial blood pressure

Answer 85

• The chemoreceptors are closely associated with the baroreceptors * Aortic body and carotid body* The chemoreceptors stimulate Hering’s nerve and the vagus nerve (similar to the baroreceptors)* Abundant blood supply via a nutrient artery* Reduced blood pressure ⇒ reduced blood flow ⇒ decreased oxygen, increased CO₂, increased H⁺* Signals elicited by the chemoreceptors excite the vasomotor centre and help to increase blood pressure* Most useful once the arterial pressure falls below 80 mmHg* Play a far more important role in respiratory control than that of blood pressure.

Question 86

Briefly describe the atrial and pulmonary artery reflexes and how they effect changes in arterial blood pressure

Answer 86

• Receptors in the atrial and pulmonary artery are called low-pressure receptors.* They operate similarly to the arterial baroreceptors* Primarily affect a change to minimise changes in pressure due to alterations in blood volume* Trigger reflex reductions in renal sympathetic stimulation * Dilation of the afferent arterioles * Decreased tubular resorption - effectively acts to reduce effective circulating volume* Atrial stretch receptors signal to the hypothalamus to decrease secretion of vasopressin * Increased water excretion * Increased GFR* Triggers release of atrial natriuretic peptide * Increase Na+ excretion

Question 87

Briefly describe the Bainbridge reflex

Answer 87

• The Bainbridge reflex is elicited with increased atrial stretch* Stretch receptors in the atria send signals to the medulla via the vagus nerve* Efferent signals return via the vagus and sympathetic trunks* Net effect is an increased heart rate and strength of contraction

Question 88

Briefly describe the CNS ischemic response

Answer 88

• The CNS ischemic response is triggered by reduced blood flow to the vasomotor centre of the medulla* Reduced blood flow causes reduced nutrient supply and ischemia* The response is generated by low blood flow, low oxygen tension and increased carbon dioxide* These changes cause direct and intesne stimulation of the vasomotor centre * Increases in the peripheral arterial blood pressure to as high as the heart can possibly cause * Marked arteriolar vasoconstriction such that some vessels become totally or almost totally occluded * Renal GFR can reduce to close to zero due to afferent arteriolar constriction

Question 89

Breifly describe the Cushing Response and underlying physiological mechanism

Answer 89

• The Cushing Response is a reaction to an increase in the pressure of the CSF surrounding the brain * Ie. this response occurs when the entire brain is under pressure, including the arteries and veins* When the CSF pressure increases beyond arterial pressure, arterial flow reduces and CNS ischaemia develops* The response is a marked increased in the systemic arterial pressure mediated by the sympathetic nervous system * In the early stages, SNS activation leads to an increased heart rate* Baroreceptors in the aortic arch detect the increase in BP and stimulate the parasympathetic nervous system leading to bradycardia* Compression of the brainstem alters the function of the respiratory centre * Irregular breathing pattern or apnea

Question 90

Why is the Cushing Reflex somewhat paradoxical

Answer 90

• The reflex trigger is likely the central chemoreceptors which lead to stimulation of the sympathetic nervous system.* The secondary marked increase in blood pressure triggers the baroreceptors which in turn stimulate the parasympathetic nervous system* While in most situations, the sympathetic and parasympathetic systems work in tandem to regulate blood pressure, during the Cushing reflex, they are both markedly activated simulataneously

Question 91

Describe the potential effects of a fluid load or blood transfusion on the total peripheral resistance and arterial blood pressure

Answer 91

• Either a fluid load or blood transfusion will increased the volume of blood within the total circulation * Not the same effect occurs with an increase in the extravascular fluid volume* Increased volume leads to increased filling pressures* Increased venous return to the heart* Increased cardiac output* Increased blood flow to all tissues * Leads to autoregulation and vasoconstriction to normalise tissue blood flow* Increased arterial blood pressure* Increased filtration pressure at the kidney * Increased pressure diuresis and natriuresis * Attempt to reduce ECV and arterial pressure

Question 92

Describe the physiological response to increased salt intakeIn which circumstances is increase salt intake likely to directly affect arterial blood pressure

Answer 92

• Increase sodium chloride intake directly increases the osmolality in the extracellular fluid* Increased osmolality * Stimulates thirst centre * Stimulates hypothalamus to secred increased quantities of ADH * Increased ADH - increase water resorption in the renal collecting duct* Net effect: * increased water intake and decreased water excretion * Expansion of the ECV and EFV* Sodium chloride levels are tightly regulated to prevent increases in arterial blood pressure as would occur above * Impaired renal function * Excessive production of anti-natriuretic hormones (aldosterone and angiotensin II)

Question 93

What are the three major serious pathophysiological complications of chronic hypertension

Answer 93

• Cardiac disease * Increased cardiac work - early heart failure * myocardial infarct (coronary artery disease - especially in humans)* Vascular accident * High blood pressure can lead to vascular accident which can be especially devastating if within the brain * Can lead to cerebral infarct or vascular rupture and bleed* Renal insufficiency * Chronic hypertension does constant damage to portions of the kidney that do not regenerate

Question 94

Describe the regulation of renin production.What is the end goal of increased renin production

Answer 94

• Renin is produced in the mural cells of the JG apparatus in the kidney - near the afferent arteriole* Renin is released in response to: * Decreases in arterial pressure * The reduction in BP is detected by the baroreceptors in the JG cells * Decreased sodium load in the distal tubule * Via signalling from the macula densa * Sympathetic nervous system activity * Increase b₁ adrenoreceptor activity* The end goal of renin release is to increase arterial blood pressure * Angiotensin II - increases vascular tone and TPR * Aldosterone - increases sodium resorption

Question 95

How is angiotensin II produced?

Answer 95

• Renin release is stimulated by a decrease in arterial blood pressure, decreases sodium load or increases activity of the sympathetic nervous system* Renin is an enzyme and cleaves angiotensinogen to the 10 amino acid peptide angiotensin I* Angiotensin I is converted to Angiotensin II by ACE that is located primarily within the lungs, but also within the kidney and blood vessels * Angiotensin is an 8 amino acid peptide

Question 96

Describe the major actions of angiotensin II

Answer 96

• Angiotensin II acts primarily to increase arterial pressure* The first major effect occurs within ~20 minutes and results in an increase in arteriolar constriction with a mild effect on venous vascular tone * This is slower than the sympathetic response delivered by neurons nad the neurotransmitters NE and Epinephrine * The increased venous tone helps improve cardiac filling and therefore cardiac output to combat the increased peripheral vascular resistance* The second major effect is to increase salt and water retention * Stimulates aldosterone production * Direct action on the kidney to increase sodium and chloride reabsorption

Question 97

How does angiotensin II directly affect an increased resorption of sodium and water

Answer 97

• Ang II increases arteriolar tone - especially the efferent * Decreased glomerular filtration pressure * Decreased renal blood flow * Decreased flow in the peritubular capillaries allows increased time for sodium resorption * Direct effect on renal tubular cells to increase sodium resorption* Note: angiotensin II also has a potent effect on the secretion of aldosterone by the adrenal gland. This has an indrect effect on the resorption of sodium and water

Question 98

Briefly describe the pathophysiological pathway for the development of hypertension as most commonly caused by chronic renal disease

Answer 98

• With chronic kidney disease, patchy areas of the kidney become disease and reduced blood flow ensues * local vascular constriction * infarcts* The diseased areas where there is reduced blood flow stimulate increased renin production* Increased renin production stimulates angiotensin II production.* Angiotensin II acts on both kidneys and the vasculature to cause increased arterial pressure and reduced GFR (due to increased tone in the efferent arteriole. * Increased vascular pressure within the glomerulus itself but reduced filtration pressure due to the differential increase in efferent arteriolar constriction

Question 99

Describe the characteristic changes caused by obesity that can lead to primary hypertension

Answer 99

1. Increased cardiac output * Increased blood flow required for increased adipose tissue * Increased metabolic demand on the gut, kidneys, heart and skeletal muscles also contributes to increased cardiac output2. Increased sympathetic nerve activity * leptin, released from adipose cells may have a direct stimulatory effect on the hypothalamus * Hypothalamus in turn has an excitatory effect on the vasomotor centre * May have a reduced baroreceptor and chemoreceptor response * especially with sleep apnoea3. Angiotensin II levels become increased * Likely primarily due to increased SNS activity * Leads to increased aldosterone also4. Chronic hypertension can lead to an impairment in the pressure natriuresis mechanism * Thereby, the kidney self-perpetuates increased pressures to ensure adequate natriuresis * Chronic reduction in blood pressure will typically improve natriuresis and renal function will improve

Question 100

Describe the three major mechanisms by which venous return alters cardiac output in the normal heart

Answer 100

1. Increased venous return to the right atrium alters output by Frank-Starling law of the heart * Increased stretch leads to increased force of contraction2. Sinus node stretch * Stretching of the SA node increases the automaticity of the node due to more rapid changes in membrane polarity * Increased heart rate3. Bainbridge reflex * Atrial stretch leads to increase inputs to the vasomotor centre in the medulla * Increased sympathetic outputs leads to an increased heart rate

Question 101

Describe the process by which a descrease in total peripheral resistance causes an increase in cardiac outputNote examples of clinical conditions that cause a reduction in TPR

Answer 101

• A reduction in total peripheral resistance leads to easier passage of blood through the capillary network and back into the venous system * As such, a decrease in TPR effects an increase in venous return* TPR will decrease in multiple circumstances * Increased tissue metabolism - physiological during exercise or pathologically with conditions such as hyperthyroidism* Hyperthyroidism * Increased metabolic drive in the tissues * Reduced total peripheral resistance * Increased heart rate * Mild hypertrophic change with chronicity* Anaemia * Reduced blood viscosity causes an effective reduction in TPR * Diminished oxygen delivery causes increased vasodilation * Increased heart rate and force of contraction as a result* AV fistula * Pathological AV fistula has the effect of reducing TPR due to creation of an “easy” pathway into the venous system

Question 102

Describe how low cardiac output reduces total peripheral resistance

Answer 102

• With reduced cardiac output there is reduced delivery of oxygen to the tissues* Autoregulatory effects at the level of the tissues lead to decreases in arteriolar tone in an attempt to increase oxygen delivery* The sum effect is a decrease in TPR* The decrease in TPR will lead to an increased venous return* The increased venous would lead to increased cardiac output in normal circumstances - compensatory heart disease* When the heart is unable to manage the increased venous return, congestive heart failure ensues* An inability of the heart to adequately provide the output to meet tissue nutrient requirements leads to forward failure

Question 103

Describe the various conditions that can lead to a reduction in cardiac output due to reduced venous return

Answer 103

• Decreased blood volume * Haemorrhage is the most common cause * Less blood present for return to the heart* Acute venous dilatation * Most often from a sudden decrease in sympathetic nervous system activity * Pooling of blood in the veins when vascular tone is reduced* Obstruction of the large veins * Internal obstruction with a thrombus or external compression by a mass* Decreased tissue mass * Especially seen in the eldery with reduced functional skeltal muscle mass* Decreased metabolic rate within the tissues * Leads to a reduction in oxygen demand * Autoregulation leads to reduced tissue blood flow (increased TPR) *

Question 104

Describe the compensatory mechanisms that are elicited during acute (global) cardiac failure

Answer 104

1. Sympathetic stimulation * Marked increased in peripheral vascular resistance to maintain arterial pressure * Increased heart rate * Increased stroke volume * Increased venous tone to increase venous return2. Renal fluid retention * Reduced renal blood flow due to decreased arterial pressure * Reduced Na⁺ and water excretion * Volume increase to help maintain arterial pressure

Question 105

Describe the potential benefits of moderate fluid retention in early heart failure

Answer 105

• Early heart failure will initially cause a reduction in arterial pressure resulting in mild decreases in renal excretion of water and sodium * Mild to moderate fluid retention ensues* Mild to moderate fluid retention leads to increased ECV* Increased ECV leads to an increase in right atrial filling pressures or mean systemic filling pressure* Increased fluid volume distends the veins leading to reduced venous resistance, easing flow back to the heart* Early fluid retention with the increased venous return can ensure near normal cardiac output with early cardiac failure

Question 106

Describe the detrimental effects of fluid retention with moderate to advanced cardiac failure

Answer 106

• In this setting, the increased fluid load has passed that necessary for compensation of reduced cardiac output.* Increased workload due to increased venous return* Over-stretching of the damaged heart due to increased filling pressures* Increased pulmonary or systemic venous pressures * Leads to pulmonary oedema or ascites/body oedema* Pulmonary oedema reduces oxygen transfer which further exacerbates increased arteriolar tone and the pressure against which the failing heart needs to contract

Question 107

Describe the vicious cycle that ensues after the onset of decompensated left sided cardiac failure

Answer 107

• Any change to the compensated steady state can trigger the cycle * Eg. increased exercise, emotional experience, severe cold, etc* Temporary increased workload outstrips capacity and left atrial pressures rise - pulmonary venous congestion* Pulmonary capillary pressure rises and small amounts of fluid begin to transudate into the interstitium and alveoli* Reduced oxygenation leads to peripheral vasodilatation - due to auto-regulatory responses* Peripheral vasodilation reduces peripheral vascular resistance and increases venous return* Increased venous return further exacerbates the increased fluid load and pressures within the lungs

Question 108

Briefly describe the flow and pressure dynamics that ensure the ductus arteriosus remains patent during foetal life and closes soon after birth

Answer 108

• The ductus arteriosus serves to shunt blood from the lungs to the aorta during foetal life.* The lungs are collapsed during foetal life. Therefore there is very high pressure within the collapsed lung and collapse pulmonary vasculature* The pressure or resistance within the aorta is lower during foetal life as increased blood flows through the placenta* As the placental flow is removed after birth, the pressure within the aorta increases* As the lungs inflate with respiration, the resistance to blood flow through the pulmonary vasculature also decreases significantly. * The initiation of respiration and occlusion of the umbilicus causes a change in the pressure differential between the aorta and pulmonary artery such that reversal of blood flow through the ductus occurs* Increased oxygen tension within the ductus stimulates contraction of the ductal smooth muscle fibres, thus reducing flow between the systemic and pulmonary circulation.

Question 109

Define circulatory shockWhat are the major causes of circulatory shock?

Answer 109

• Circulatory shock refers to inadequate blood flow through the body to provide nutrients, especially oxygen, such that the tissues are damaged as a result* Cardiac Shock: * Reduced ability of the heart to pump blood forward for numerous reasons - cardiogenic shock * Reduced venous return * Reduced blood volume (hypovolaemic shock) * Diminished venous tone (neurogenic shock or anaphylactic shock) * Large vein obstruction* Non-cardiac shock * Increased / excessive tissue metabolic rate * Abnormal tissue perfusion patterns * Septic shock

Question 110

Describe the initial protective mechanisms induced in early hypovolaemic shock

Answer 110

• Initial blood loss leads to reduced venous return and subsequent reduced cardiac output* Reduced cardiac output leads to a mild reduction in arterial pressure* Reduced pressure is rapidly detected by the baroreceptors in the aortic arch and carotid body* The baroreceptors trigger the sympathetic system via reduced inhibition in the vasomotor centre within the medulla* SNS activation leads to * Increased rate and force of cardiac contraction - increased cardiac output * Arteriolar constriction - maintenance of blood pressure * Minimal constriction of the coronary and cerebral circulation * Increased venous tone - reduces venous capacitance and increases venous return, countering for the loss of blood volume.

Question 111

List the 7 major mechanisms that enable compensation following acute non-life threatening hypovolaemic shock

Answer 111

1. Baroreceptor reflex * SNS stimulation2. Central nervous system ischaemic response * powerful SNS activation, but not elicited in mild cases of shock3. Reverse stress-relaxation * arteriolar smooth muscles slowly contract to reduce capacitance and ensure adequate filtration pressure at the capillary4. Increased secretion of renin - activation of the RAAS * Decreases salt and water loss5. Secretion of ADH / vasopressin * Vasoconstriction and greatly enhances water resoprtion in the renal collecting duct6. Increase secretion of NE and epinephrine by the adrenal * Augments the SNS effects7. Other compensatory mechanisms * Resorb fluid from the interstitial space * Resorb fluid from the GIT * Increased thirst and salt appetite

Question 112

Describe the basic processes that occur during progressive shock

Answer 112

• With severe shock, a progressive or positive feedback loop ensues where the physiological changes contribute to worsening of cardiac function and worsening of the shock* Arterial blood pressure falls - coronary artery flow reduces - reduced nutrition to the myocardium worsens cardiac output * This effect does not show up clinically early in the course of shock due to the large volume of cardiac reserve* Vasomotor failure * Reduced arterial pressure to the vasomotor centre triggers a marked SNS response. This response deteriorates over time and with reducing arterial pressures. Failure tends not to occur unless the arterial pressure drops below ~30 mmHg* Microvascular occlusion and sludging of blood * Reduced blood flow through the microvasculature causes a build up of waste products and acidity. This can cause local tissue ischaemia and local agglutination. Small clots can occlude vessels reducing flow of nutrients to tissues* Increased capillary permeability * Occurs in late stage shock in a response to prolonged capillary hypoxia* Toxin release by ischaemic tissue * Includes histamine, serotonin and cellular enzymes* Cardiac depression due to endotoxin * A major cause of spetic shock * Can be seen with reduced GIT blood flow leading to GIT wall compromise and increased translocation of luminal contents* Generalised cellular deterioration * Especially in the highly metabolically active liver* Patchy tissue necrosis * Mainly due to the reduced nutrient supply at the venule end of the capillary * Can lead to hepatic necrosis, tubular necrosis in the kidney, myocardial infarction and lung injury* Acidosis * Reduced oxidative metabolism and increased glycolysis leads to lactic acid buildup * Redcued CO₂ removal leads to carbonic acid accumulation

Question 113

Describe the basic physiological process caused by neurogenic shockGive examples of causes of neurogenic shock

Answer 113

• Neurogenic shock is caused by a sudden loss of sympathetic tone.* Reduced sympathetic tone with maintenance of vagal tone leads to: * Markedly reduced venous tone and increased peripheral capacitance * Marked reduction in venous return and cardiac output * Flushing of the skin * Reduced heart rate possible* Causes can include * Deep anaesthesia with depression of the vasomotor centre * Spinal anaesthesia especially when this extends high - depression of the SNS outflow from the spinal cord * Brain damage / trauma - initial activation of the vasomotor centre will cease after >5-10 minutes if ischaemia is prolonged, leading to inactivation

Question 114

Define anaphylactic shockDescribe the physiological consequences of anaphylactic shock

Answer 114

• An extreme, often life-threatening allergic reaction to an antigen to which the body is hyper-reactive* Generally results from an antibody-antigen reaction in a previously sensitised individual* Primarily elicits a type 1 (IgE mediated) immune response with release of histamine and histamine-like substances from the basophils and mast cells * Marked venous dilatation - reduced venous return and cardiac output * Arteriolar dilatation - reduced arterial pressure * Marked increase in capillary permeability * leakage of high protein fluid into the interstitial space * Histamine can also reduce the normal SNS response

Question 115

Define septic shock

Answer 115

• Septic shock is a condition triggered by the dissemination of an infectious agent (usually bacteria) or the product of an infectious agent (endotoxin) that leads to a marked reduction in blood pressure leading to insuffient nutrient delivery (especially oxygen) to the tissues

Question 116

Describe the special features of septic shock not seen with other forms of shock

Answer 116

1. High fever2. Marked vasodilation3. High cardiac output * Increased metabolic demand and arteriolar dilatation (autoregulatory mechanism) * Bacterial or endotoxin stimulation of cellular metabolism4. Sludging of blood and auto-agglutination * Seen earlier with septic shock than in other forms5. Development of DIC * May lead to widespread intra-tissue haemorrhage

Question 117

The kidneys primary role is that of water and electolyte homeostasis together with waste excretion.What are the numerous other homeostatic functnios performed by the kidney?

Answer 117

• Regulation of arterial blood pressure * Primarily through activation of the RAAS* Regulation of acid-base balance * Control of hydrogen ion and HCO₃^- excretion* Regulation of red blood cell production * Production of EPO* Secretion, metabolism and excretion of various hormones * Especially formation of 1, 25-dihydroxyvitamin D₃ (calcitriol)* Gluconeogenesis

Question 118

What are the major wast products excreted by the kidneys, and from where are they derived?

Answer 118

• Urea * From amino acid breakdown* Creatinine * From muscle phosphocreatine* Uric acid * From nucleic acid metabolism* End products of haemoglobin breakdown* Metabolites of various hormonesAlso responsible for elimination of the majority of toxins and foreign substances that are ingested by the body

Question 119

Describe the innervation of the bladder

Answer 119

• Principle nerve supply via the pelvic nerves * Segments S2-S3 of the spinal cord * Sensory and motor fibres present * Sensory nerves detect stretch in the bladder neck * Motor nerves - parasympathetic and innervate the detrusor muscle and internal urethral sphincter* Pudendal nerve * Arises from the S2-S3 segment of the spinal cord * Innervates skeletal muscle fibres in the external urethral sphincter * Somatic nerve fibres innervating voluntary skeletal muscle* Hypogastric nerve * Sympathetic nerve arising from L1-L4 * NE neurotransmitter * Acts on beta receptors on the detrusor muscle (relaxation when active) * Acts on alpha receptors in the internal urethral sphincter (contraction when active)

Question 120

Describe the neurological pathway that initiates and controls micturition

Answer 120

1. The bladder fills to a critical point - bladder filling is sensed by the afferents in the pelvic nerve (parasympathetic)2. The signal transmitter by the pelvic nerve travels up the spinal cord to the micturition centre in the pontine micturition centre3. Signals transmit between the pons and the cerebral cortex and hypothalamus to enact voluntary control4. If appropriate, signals are sent via the parasympathetic (pelvic) nerve to initiate detrusor contraction via ACh release5. Simultaneously, inhibitory signals reduce sympathetic tone allowing appropriate detrusor contraction and causing relaxation of the urethral sphincter

Question 121

Describe the filtration unit of the kidney, the glomerulus

Answer 121

• Tuft of capillaries supplied by the afferent arteriole* The filter is made up of: * The capillary endothelium * The basement membrane * A layer of epithelial cells surrounding the BM * Podocytes* Thousands of fenetrations in the endothelium* Negative charge of the endothelium helps limit protein filtration* BM: loos connective tissue (collagen) and proteoglycan network - also negatively charged* Podocytes are separates by slit pores and also negatively charged

Question 122

List the glomerular diseases that have been documented in dogs and cats

Answer 122

1. Membranous nephropathy2. Membranoproliferative glomerulonephritis3. Proliferative glomerulonephritis4. Imunoglobulin A nephropathy5. Amyloidosis6. Hereditary Nephritis7. Minimal change disease8. Glomerulosclerosis

Question 123

Describe the various pathophysiologcal processes that cause the different glomerular diseases

Answer 123

1. Immune complex formation and deposition * eg. subendothelial side of the basement membrane in membranoproliferative glomerulonephriti s * Binding of antibodies to the subepithelial side in membranous nephropathy * Anti-glomerular basement membrane complexes * Described in humans with proliferative glomerulonephritis2. Proliferation of the endocapillary or mesangium * Described for proliferative glomerulonephritis and immunoglobulin A nephropathy3. Amyloidosis * Protein deposits are seen primarily within the glomerulus, except in the Shar Pei and Abyssinian (renal medulla)4. Inherited collagen type IV defects * Early deterioration of the basement membrane (which is primarily composed of type IV collagen) * Seen in hereditary nephritis in English Cocker Spaniel, dalmation, Springer Spaniels and Bull Terrier. X-linked form in Samoyed dogs5. Minimal change disease - triggered by increased production of lymphokines by dysfunctional T cells * loss of negative charge alters podocyte foot process * selective loss of albumin6. Glomerulosclerosis - thickening/scarring of the glomeurlar capillies. Tends to be segmental / focal

Question 124

Describe the process whereby increased glomerular filtration of protein causes tubulointerstitial cell damage

Answer 124

• Increased protein can be filtered by the glomerulus ddue to numerous different underlying mechanisms* Increased protein (less so albumin) within the renal tubules needs to be resorbed by the proximal tubules* The process of protein resorption increases the workload of the tubular epithelial cells* The proteins can be cytotoxic * The combination of cell damage and increased cell workload can lead to cell death* Protein casts can slow tubular flow and cause obstruction and increased tubular pressures* Glomerular injury can lead to reduced perfusion of the tubular region due to reduced blood flow from the efferent arteriole

Question 125

Describe how GFR can be altered

Answer 125

• Glomerular blood flow can be increased by either * Increasing cardiac output * Decreasing arteriolar tone (reducing hydrostatic pressure)* GFR can be reduced by: * Increases in Bowman’s capsule hydrostatic pressure * Reduced cardiac output * Increased afferent arteriolar tone * Increased glomerular capillary colloid osmotic pressure

Question 126

Briefly list and describe the effects various hormones that can impact renal blood flow

Answer 126

• Epinephrine and norepinephrine * Parallel the effects of the sympathetic nervous system * Vasoconstriction effects largely balanced by autoregulatory effects at the tissue level* Endothelin * Potent vasoconstrictor that is released in response to vascular injury * Also released / increased in certain disease states* Angiotensin II * Mostly constricts the efferent arteriole * Afferent is relatively protected by prostaglandins and nitric oxide * Increases glomerular hydrostatic pressure while reducing renal blood flow * Helps preserve GFR during periods of low arterial pressure * Low blood flow in the peritubular capillaries helps to increase sodium and water resorption* Nitric Oxide * Potent vasodilator helps to maintain renal blood flow and therefore GFR* Prostaglandins and bradykinin * Vasodilatory effect on arterioles - especially on the afferent arteriole * Help to counter the effects of SNS and AT II

Question 127

What is the purpose and drive of tubuloglomerular feedback?

Answer 127

• Tubuloglomerular feedback helps link changes in sodium concentration in the distal tubules to renal arteriolar blood flow, autoregulation and GFR* This feedback loop helps to deliver a constant flow of sodium chloride to the distal tubule preventing spurious fluctuations that would otherwise occur

Question 128

Describe the tubuloglomerular feedback mechanism

Answer 128

• The mechanism has two components that work together to control GFR * Afferent feedback mechanism * Efferent feedback mechanism* The juxtaglomerular complex consists of the macula densa cells within the proximal portion of the distal convoluted tubule and JG cells in the walls of the afferent and efferent arterioles * The macula densa cells have secretory vescicles that are directed towards the arteriolar walls* Decrease macular densa NaCl causes dilation of the afferent arterioles and increased secretion of renin * Decreased NaCl at this site occurs with increased NaCl resorption in the loop of Henle due to reduced flow rate1. Increased flow at the afferent arteriole increases GFR2. Renin → AT II → efferent arteriole constriction → increased GFR*

Question 129

Describe the physiological mechanism as to why high protein intake and hyperglycaemia increase renal blood flow and GFR

Answer 129

• Protein is digested to release amino acids into the circulation.* Amino acids and glucose are both resorbed from the proximal renal tubules back into the blood stream * This transport occurs in conjunction with sodium * Increased AA or glucose absorption also increases sodium resorption* This leads to less sodium in the ascending loop of Henle and at the macula densa* Low sodium is detected at this site and tubuloglomerular feedback leads to arteriolar dilatation, increase in renal blood flow and GFR

Question 130

List six situations / conditions in which renal blood flow and glomerular filtration are increased

Answer 130

1. High salt diet2. High protein diet3. Diabetes mellitus4. Obesity - early prior to potential renal damage5. Glucocorticoid excess (endogenous or exogenous)6. Fever - due to circulating pyrogens

Question 131

Describe the process of active transport required for sodium resorption in the renal tubule

Answer 131

• Na/K ATPase pumps sodium from the cell into the interstitial space. * 3 sodium out of the cell, 2 potassium into the cell * Sodium is maintained at a high concentration in the interstitium and can diffuse back into the peritubular capillary* This process creates a low sodium concentration and a negative within the tubular cell* High sodium concentration in the tubular fluid can then diffuse passively into the tubular cell* In the proximal convoluted tubule, a dense brush border increases the luminal side surface area by ~ 20 fold * Carrier proteins in the proximal convoluted tubule also allow for facilitated diffusion of sodium at this site * This is important for secondary active transport of amino acids and glucose

Question 132

Describe the processes that cause paradoxical aciduria with gastric outflow tract obstruction

Answer 132

• GOO causes vomiting and subsequent loss of chloride and acid together with total water volume* The result is dehydration with hypochloraemia and a metabolic alkalosis* Reduced blood flow in the afferent arteriole ⇒ reduced GFR if not for increased renin release.* Increased renin ⇒ increased angiotensin II and aldosterone* Aldosterone and dehydration drive sodium resorption to help improve ECV and BP* Active transport and counter transport of sodium occurs with Na exchanged for hydrogen ions in the proximal tubule * Sodium concentration and water volume are maintained at the expense of acid loss* Total effect - hypochloraemic metabolic alkalosis with excess H+ ions in the urine - paradoxical aciduria

Question 133

Describe the processes that allow absorption and / or secretion in the proximal tubule

Answer 133

• Sodium * active transport down a concentration gradient * Concentration gradient is maintained by the Na/K ATPase pump on the basolateral membrane* Glucose * Secondary active transport via the SGLT (sodium glucose transported into the tubular cell * Pumped out of the cell via the GLUT into the interstitial space at the basolateral membrane* Phosphate * Secondary active transport via sodium dependent P(i) cotransporters * Regulated by fibroplast growth factor-23 (FGF23) * Increased PTH and FGF23 both decrease the resorption of phosphate by the cotransporters* Amino acids * Secondary active transport by sodium dependent SLT5 (solute carrier family protein)* Free water - absorbed via osmosis and coupled to sodium transport

Question 134

Describe the processes that allow absorption and / or secretion in the loop of Henle

Answer 134

Descending Limb:* Water: * resorption primarily via aquaporin channels * Helps to deliver a concentrated urine to the ascending limb for solute resorption_Thick Ascending Limb_* Sodium: * Co-transport with chloride and potassium via the NKCC2 symporter* Potassium - via NKCC2 symported * Potassium also leaks back into the lumen contributing to a mild positive charge of the luminal fluid * This positive charge helps for drive cations out of the lumen into the cells (calcium, magnesium)* Chloride - via NKCC2 symported* Nodium and hydrogen counter-current exchange* Relatively impermeable to water* Calcium, bicarbonate and magnesium also resporbed* * As the above electrolytes are removed, the urine becomes more dilute* Delivers luminal fluid to the macula densa where the sodium concentration is sensed

Question 135

Describe the processes that allow absorption and / or secretion in the distal convoluted tubule

Answer 135

• Sodium * Na⁺K⁺ ATPase pump continues to maintain a concentration gradient * Sodium diffuses down the concentration gradient primarily via the NCC cotransporter* Chloride * Primarily reabsorbed together with sodium via the NCC * Chloride channels in the basolateral membrane allow for diffusion out of the cell* Calcium* Magnesium

Question 136

Describe the processes that allow absorption and / or secretion in the late distal convoluted tubule and collecting ducts

Answer 136

• Principle cells * Resorb sodium in exchange for potassium * K+ gradient is generated by the Na⁺K⁺ ATPase pump in the basolateral membrane * Site of action of aldosterone and therefore the aldosterone receptor blocker spironolactone * K+ leaves the cell into the duct lumen down a concentration gradient via K⁺ channels * Na resorption from the lumen via Na⁺ channels* Intercalated cells * Major role in acid base regulation * H+ secreted in type A cells via: * H⁺-ATPase (against large concentration gradient) and H⁺Na⁺ exchanger * These cells produce bicarbonate for resorption * Type A cells resorb potassium and excrete chloride * Type B cells * Chloride bicarbonate counter-transporter secretes bicarbonate * Resorb chloride and secrete potassium* Water resorption is controlled largely by ADH regulation of aquaporin channels

Question 137

List the various mechanisms by which tubular resorption can be controlled

Answer 137

1. Glomerulotubular balance * Increased GFR - increased tubular resorption2. Peritubular capillary and renal interstitial forces * Changes in capillary hydrostatic pressure can influence hydrostatic and osmotic pressure in the interstitium3. Arterial pressure * Effects urine output by pressure diuresis and pressure natriuresis4. Hormonal control * Aldosterone promotes sodium resorption and potassium excretion * Angiotensin II increases sodium and water retention * ADH increases water resorption * ANP decreases sodium and water resorption * Parathyroid hormone increases calcium resorption * FGF23 increases phosphorus reabsorption, decreases calcium reabsorption5. Sympathetic nervous system * Increases sodium reabsorption

Question 138

Describe the mechansims by which the renal medullary concnetration gradient is established

Answer 138

1. Active transport of sodium and co-transport of potassium, chloride and other ions out of the thick ascending loop of Henle2. Active transport of solutes from the collecting duct into the interstitium3. Facilitated diffusion of urea from the collecting ducts into the medullary interstitium4. Diffusion of only small volumes of water from the medullary tubules into the interstitium

Question 139

Describe how urea excretion and reabsorption contributes to the medullary concentration gradient.

Answer 139

• Urea is filtered freely at the glomeruus into the tubular fluid.* 40-50% of the filtered urea is resabsorbed in the proximal tubule - though this movement is less than water and the actual urea concentration increases* The loop of Henle and the distal tubules and cortical collecting duct are essentially impermeable to urea * Urea is UT-A2 secretes urea into the thin loop of Henle* Urea can diffuse down a concentration gradient from the medullary collecting duct * Diffusion is greatly facilitated by the urea transporters UT-A1 and UT-A3.* The urea transporters are activated by ADH, increasing urea transport* Urea moves simulataneously with water under the influence of ADH * This allows the final urea concentration within the urine to remain relatively constant

Question 140

What is the effect of low blood urea on the renal medullary concentration gradient and urine concentration?

Answer 140

• With low blood urea from what ever cause, there is less net movement of urea from the medullary collecting into the medullary interstitium.* As urea contributes ~40-50% of the osmolarity to the interstitium, less urea means the a smaller concentration gradient in the loop of Henle* The smaller concentration gradient means water resorption is reduced* Reduced water resorption leads to a lower USG and increased urine production to continue excretion of solutes such as sodium at a constant rate

Question 141

Briefly describe the process of the osmoreceptor-ADH feedback system to changes in plasma osmolarity

Answer 141

• Osmoreceptors in the anterior hypothalamus shrink slightly with increases plasma osmolarity (~increased sodium)* The osmoreceptors fire nerve signals to the supraoptic nuclei* These messages are relayed to the posterior pituitary gland* ADH is released from secretory vesicles in the posterior pituitary* ADH circulates in the blood to the kidney * Causes vasoconstriction also* ADH stimulates increased expressioin of the aquaporin channel in the distal convoluted tubule, cortical collecting tubules and medullary collecting duct* Increased free water resorption * Concnurrent increased urea resorption to increased the medullary concentrating gradient* Increased water resorption - low urine output - highly concentrated urine

Question 142

List and describe the major stimulators of thirst

Answer 142

1. Increase plasma osmolarity * Causes intracellular deydration (cell shrinkage) of osmoreceptors in the thirst centres of the brain2. Decreased arterial blood pressure / extracellular fluid volume * Likely due to neural inputs from the baroreceptors3. Angiotensin II * This peptide directly stimulates regions of the thirst centre4. Dry mouth5. Gastrointestinal and pharyngeal stimuli influence thirst * Predominantly these stimuli limit thirst - partial relief occurs with stimuli of the pharynx and stomach after drinking. This helps to temper the thirst response and minimise the risk of over-hydration

Question 143

Briefly explain the relative importance of the ADH-thirst response and the Angiotensin II - Aldosterone system for maintenance of extracellular fluid osmolarity

Answer 143

• ADH/thirst mechanisms directly affect the quantity of free water absorbed or reabsorbed into the body * This occurs either via the kidney or GIT respectively* The addition or reabsorption of free water into the extracellular fluid via both of these mechanisms has a marked and rapid effect on the concentration of solutes within this space - ie. direct effect on the osmolarity* Angiotensin II can directly impact the thirst centre* However, the majority of the effect of AT II and aldosterone is to improve or enhance sodium reabsorption in the kidney (especially the distal convoluted tubule).* Sodium reabsorption in the kidney also leads to water reabsorption via osmosis* Thus, these hormones cause an increase in extracellular fluid volume with minimal change to the sodium concentration * Minimal effect on the osmolarity

Question 144

Describe briefly how hypoaldosteronism leads to decreased plasma sodium

Answer 144

• Aldosterone helps to uprgulate the action of the Na⁺K⁺ATPase pump in the distal convoluted tubule.* The action of this pump helps to maintain a sodium concentration gradient between the tubular fluid and intracellular fluid promoting movement of sodium from the tubular fluid into the tubular cells down a concentration gradient. * ie. aldosterone helps enhance sodium reabsorption* Is sodium is not reabsorbed, then both sodium and water are lost in the urine* Dehydration is initially accompanied by normo-osmolar plasma and extracellular fluid* This fluid loss leads to stimulation of the thirst centre and replacement of ECF loss with free water* Ongoing loss of sodium, replaced by free water eventually reduces the plasma and ECF osmolarity* Reduced sodium can further lead to reduced urine concentration and increased free water loss due to a reduction in the medullary concentration gradient

Question 145

List the various machanisms or situations by which potassium will move between the extracellular and intracellular fluid compartments

Answer 145

Potassium moves into the cellular fluid compartment:* Insulin* Aldosterone* b-adrenergic stimulation* AlkalosisPotassium moves into the extracellular fluid compartment with the opposite of the above:Lack of insulin or aldosterone and b-adrenergic blockade together with acidosis.

Question 146

Briefly overview the excretion of potassium as it passes through the kidney (nephron)

Answer 146

• Renal potassium excretion is determined by the GFR and the rate of both potassium reabsorption and secretion within the tubules * GFR and filtration is relatively constant in a healthy animal* 65% of filtered potassium is reabsorbed in the proximal tubule* 25-30% is reabsorbed in the loop of Henle (especially the thick ascending limb) - via NKCC2 symporter* The collecting tubules can reabsorb or secrete potassium and are responsible for the majority of excretion control based on daily potassium intake * Excretion driven by action of the Na⁺K⁺ATPase in the principle cells * Potassium moves out into the tubular fluid via the “big potassium channel” and the ROMK (renal outer medullary potassium channel)* The type A intercalated cells reabsorb potassium in exchange for chloride

Question 147

Describe the 4 major mechanisms that help to stimulate potassium secretion during a period of hyperkalaemia or with increased potassium intake

Answer 147

1. Increased activity of the Na⁺K⁺ATPase pump inthe distal tubule * Increases potassium uptake into the cell increases the diffusion gradient into the luminal fluid2. Increased ECF potassium reduces the backleak of potassium from the cells into the ECF3. Increased synthesis of potassium channels in the luminal membrane - ROMK and big potassium channels4. Increased aldosterone secretion - upregulates the action of the Na⁺K⁺ATPase pump which facilitates movement of potassium into the cell and down the diffusion gradient as in 1.

Question 148

Describe how acidosis and alkalosis effect potassium secretion

Answer 148

• Acidosis leads to an increase in hydrogen ion buildup in the interstitial space and cellular fluid* H+ is exchanged for potassium via the H⁺K⁺ATPase in the luminal membrane of the type A intercalated cell. * Increased acid therefore leads to exchange with potassium and increased reabsorption of K⁺* Acidosis also inhibits the Na⁺K⁺ATPase in the basolateral membrane * Reduced intracellular potassium increases the diffusion gradient from the luminal fluid into the cell

Question 149

Describe the processes of renal calcium filtration and reabsorption

Answer 149

• Calcium is ~40% bound to protein and ~10% bound to phosphate and citrate * ~50% of the plasma calcium is ionised free calcium * Only ionized calcium is filtered at the glomerulus* ~65% is filtered at the proximal tubule, predominantly via the paracellular route dissolved in water * ~20% diffuses through the cell down an electrochemical gradient * Exits the basolateral membrane via Ca⁺⁺ATPase pump and by sodium-calcium counter transport* Thick ascending limb - 50% resorbed via the paracellular route * 50% via transcellular route - mediated by PTH* Distal tubule - PTH mediated active transcellular transport

Question 150

Describe the action of PTH on renal calcium resorption / secretion

Answer 150

• Plasma calcium concentration is sensed by the calcium-sensing receptors on the parathyroid gland * Increased calcium - increased CSR activity - decrease PTH release * Decreased calcium - decreased CSR activity - increased PTH release* Increased PTH stimulates increased calcium reabsorption primarily in the distal convoluted tubule* PTH regulates expression and function of two proteins responsible for transcellular calcium transport

Question 151

Briefly describe the renal control mechanisms that can affect the reabsoprtion or exretion of phosphate

Answer 151

• The rate of phosphate excretion is largely controlled by a spill-over mechanism. * Basically: Increased serum phosphate is filtered at the glomerulus and once the threshold for resorption is reached, the remainder is excreted in the urine* The proximal tubule resorbs 75-80% of filtered phosphate * Primarily via co-transport with sodium from the lumen* The distal tubule resorbes ~ 10% of the filtered phosphate* ~ 10% of filtered phosphate is excreted in the urine* PTH decreases the expression of the sodium-phosphate co-transporter in the apical membrane* FGF23 triggers internalisation and degradation of the sodium-phosphate co-transporter - reduces phosphate reabsorption. * Also reduces vitamin D synthesis, thereby reducing phosphorus absorption in the gut.

Question 152

List the various diuretics and their respective site/method of action

Answer 152

1. Osmotic diuretics: eg. mannitol * filtered by the glomerulus but not resorbed in the tubules. Acts to draw water into the tubules or at least prevent reabsorption2. Loop diuretics: eg. frusemide * Blocks the NKCC2 co-transporter. Increases solute delivery to the distal convoluted tubule - maintains osmotic gradient within the luminal fluid. Impairs countercurrent exchange in the loop of Henle3. Thiazide diuretics: eg. hydrochlorothiazide * NaCl cotransporter blockade * Reduces Na+ resorption in the distal convoluted tubule4. Carbonic anhydrase inhibitors: eg. acetazolamide * Blocks conversion of CO₂ and H₂0 to H⁺ and bicarbonate especially in the proximal tubules * Reduces H⁺ exchange for sodium in the distal tubules * Redcued bicarbonate and sodium reabsorption * Subsequent acidosis5. Aldosterone receptor antagonists: eg. spironolactone * Block effect of aldosterone on the Na⁺K⁺ATPase pump and potassium channels6. Sodium channel blockers: eg. triamterene * Blocks the sodium channel in the collecting tubules * Subsequent decrease in Na⁺K⁺ATPase activity and reduced potassium excretion

Question 153

Describe the major physiological effects of an acute kidney injury

Answer 153

• Marked reduction in renal blood flow and glomerular filtration rate* Reduced GFR: * Reduced excretion of waste products such as urea / creatinine * Inability to excrete solutes such as sodium, potassium and hydrogen ions * Impaired ability to excrete water* Retention of solutes and water leads to volume / fluid overload and hypertension* Increased potassium reduces membrane excitability* Inability to remove acid can aggravate hyperkalemia

Question 154

What is the basic cause for a loss of renal concentrating ability due to pyelonephritis?

Answer 154

• Pyelonephritis can be caused by the blood stream, but is more often caused by ascending infection for the bladder * This is allowed due to vesicoureteral reflux duringh micturition* Infection (often E coli) invades the renal pelvis initially* The localisation within the renal pelvis and calyxes leads to medullary inflammation* Medullary inflammation can markedly affect the countercurrent mechanism for concentrating urine in both the loop of Henle and the collecting ducts * This leads to a marked reduction in concentrating ability

Question 155

Why may azotemia not be seen with early pyelonephritis?

Answer 155

• As the infection initially involed the medulla, there is no affect on the function of the glomerulus and cortical tubules* Filtration of the blood occurs normal and the normal portion of the urea is reabsorbed at the proximal tubules* Recycling of urea is reduced, leading to more dilute urine.* Increased urine output offsets the reduction in urea concentration* Creatinine is freely filtered and secreted into the proximal tubules. As creatinine is not reabsorbed from the tubules, creatinine levels remain normal unless there is damage to the proximal tubular or glomerular function

Question 156

Describe the major functions of the red blood cells

Answer 156

• Oxygen delivery to tissues* Acid-base buffer of the whole blood* Delivery of CO2 to the lungs for expiration

Question 157

Describe the basic enzymes and processes that enable the red blood cell to act as an acid-base buffer for the whole blood

Answer 157

• RBCs contain large quantities of carbonic anhydrase * This enzyme catalyses the reversible reactionH₂0 + CO₂ ⇔ H₂CO₃ (carbonic acid) ⇔ H⁺ + HCO₃^-* The reaction catalysed by carbonic anhydrase is extremely rapid* This reaction allows rapid transfer of excessive tissue CO₂ to the lungs where expiration of CO₂ reduces the concentration and drives the equation to the left

Question 158

Describe the role of cobalamin and vitamin B12 in the production of RBCs.What RBC abnormality results from deficiency of Vit B12 and cobalamin

Answer 158

• Vitamin B12 and cobalamin are essential for DNA synthesis* Both are required for the adequate formation of thymidine triphosphate * Thymine is one of the purine bases that is an essential DNA building block* As the RBC production is rapid and turnover constant, reduction in the available DNA building blocks reduces the rate of RBC cell division and maturation* This leads to reduced RBC production and the RBCs that are produced have not matured sufficiently* Poorly matured red blood cells are large, fragile, oval shaped *macrocytes** These macrocytes have a short life - 1/3 - 1/2 of normal

Question 159

What are the major functions of the tissue macrophages

Answer 159

*

Question 160

What is the defined role of the reticuloendothelial system?

Answer 160

• The reticuloendothelial system (RES) is a heterogeneous population of phagocytic cells in systemically fixed tissues that play an important role in the clearance of particles and soluble substances in the circulation and tissues

Question 161

What are the components of the reticuloendothelial system and where are they located

Answer 161

• The RES is primarily composed of tissue macrophages * Monocytic cells that have migrated into the tissues, expanded / increased in size become adapted to form specific functions based on their location* Specialised endothelial cells, especially liver sinusoidal endothelial cells also actively participate in the clearance of small particles from the body* The macrophages of the RES are located in most organs, but are particularly dense in the following: * Skin / subcutaneous tissue * Lymph nodes * Lungs - alveolar macrophages * Liver - Kupffer cells * Spleen - within the trabecular network and venous sinuses of the red pulp * Bone marrow

Question 162

Describe the broad complex of tissue changes that occurs during inflammation

Answer 162

1. Vasodilation of the local blood vessels * Increased local blood flow2. Increased vascular permeability * Allows for leakage of fluid into the interstitial space3. +/- Clotting of the fluid within the interstitial space * primarily due to increased amounts of fibrinogen and other proteins4. Migration of granulocytes and monocytes * Driven largely by chemotactic factors released during inflammation * Activation of the phagocytic system of both neutrophils and macrophages5. Swelling of the tissue cells

Question 163

List the major important mediators of inflammation and the basic role of each

Answer 163

1. Histamine * Increases capillary permeability2. Bradykinin * Primary effect is vasodilation, but also contributes to increases in vascular permeability3. Serotonin * Released from platelets during inflammation and at small quantities stimulates vasodilation * With increased release, vasoconstriction and platelet aggregation occurs4. Prostaglandins * PGI₂ is a vasodilator and inhibits platelet aggregation5. Complement system - several reaction products6. Coagulation system - several reaction products7. Lymphokines * Activate and regulate the immune response * Stimulate chemotaxis * Aid B cells to produce antibodies

Question 164

Briefly describe the process whereby neutrophils migrate out of the blood into inflammed tissue

Answer 164

• Neutrophil invasion of an inflammed site begins within the first hour or so* Inflammatory cytokines attract neutrophils to the site * IL-1, TNF and other inflammatory products* Increased endothelial cell expression of adhesion molecules * iCAM - intercellular adhesion molecule - 1 * Selectin* Integrin molecules on the neutrophil interact and bind to the adhesion molecules on the endothelium * This causes margination of the neutrophil* The inflammatory cytokines increase vascular wall permeability * Increased space between the endothelial cells allows for diapedesis of the neutrophils into the tissue* Inflammatory mediators then cause chemotaxis and neutrophils migrate via ameboid movement within the interstitial space* The mature neutrophils are ready primed to begin their scavenging function

Question 165

Describe the first line defence systems offered by macrophages during inflammation

Answer 165

• The initial macrophage response is carried out by the tissue macrophages * ie. the macrophages that are already mature and ready to perform their scavenging function* The macrophages enlarge during inflammation* Previously sessile macrophages can break away from their tissue attachment and move more freely through the tissue* There are limited numbers of macrophages in the tissues to provide this first line of defence

Question 166

Describe the third line of defence that macrophages provide during tissue inflammation

Answer 166

• Monocytes enter an inflammed area in a similar manner to the neutrophils * Circulating and storage pool of monocytes is smaller than the neutrophils* Once in the tissues, monocytes take ~8 hours to swell and produce abundant lysosomes to enable their phagocytic actions* It takes several days to weeks for the bone marrow to produce more monocytes such that they can predominate in the inflammatory response* These macrophages can also initate the development of antibodies

Question 167

What is a neutrophil extracellular trap?What are the known roles of the NETs?

Answer 167

• Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. * NETs are formed by release of granule proteins and chromatin to form an extracellular fibril matrix​* The NETs comprise a high concentration of antimicrobial proteins such as elastase, cathepsin G and histones** May serve as a physical barrier to microbial migration They serve to trap and prevent widespread diffusion and damage from the proteases released by the neutrophils

Question 168

Describe the known role of NETs (neutrophil extracellular traps) during sepsis

Answer 168

• With overwhelming infection such as seen with sepsis, NETs have been shown to form within the capillaries * This occurs specifically within the liver sinusoids and the alveolar capillaries* The formation of intravascular NETs is tightly controlled by platelets * Platelets sense severe infection with TLR-4 * They then bind to and activate neutrophils * Platelet activated neutrophil NET formation is rapid, occurring within minutes* Intravascular NETs have been documented to trap intravascular bacteria as they pass through the vessels

Question 169

Describe the activation pathway for NETosis

Answer 169

• Thought to begin with activation of the NADPH oxidase ensyme in the plasma membrane* This activates protein-arginine deiminase 4 (PAD4) via ROS* PAD4 alters the histones in DNA by citrullination * This results in decondensation of the nuclear DNA* Azurophilic granule proteins then enter the nucleus resulting in further decondensation and rupture of the nuclear envelope* Chromatin enters the cytoplasm and additional granule and cytoplasmic proteins are added to the NET* The next process depends on the activation trigger - suicidal or vital NETosis ensues

Question 170

Describe the process of suicidal NETosis

Answer 170

• Neutrophils form the NET intracellularly followed by rupture of the plasma membrane.* This results in release of the NET and death of the cell * This cell death is different from both apoptosis and necrosis* Activated when ligands such as antibodies bind with TLR’s, Fc receptors and complement receptors * This activation triggers the influx of calcium and activation of the NETosis pathway* The process can take hours even with potent stimulation

Question 171

Describe the process of vital NETosis

Answer 171

• Stimulated by bacterial LPS, other bacterial products and TLR4-activated platelets or complement proteins in tandem with TLR2* Vital NETosis results in bledding of the nucleus and formation of a DNA filled vesicle* This DNA filled vesicle is exocytosed leaving the plasma membrane intact* This process does not result in cell death, but there is a reduction in the cell DNA volume * The neutrophil can continue performing phagocytosis and kill microbes after vital NETosis

Question 172

List the 5 most important factors that help stimulate the bone marrow response in the face of persistent inflammation

Answer 172

1. Tumour necrosis factor2. IL-13. Granulocyte-monocyte colony stimulating factor4. Granulocyte colony stimulating factor5. Monocyte colony stimulating factor

Question 173

Describe the mechanisms by which eosinophils can mitigate a parasitic infection

Answer 173

• Eosiniphils display chemotaxis to areas of parasitic infestation * IL-5 and eotaxin enhance eosinophil chemotaxis * This occurs as a part of a Th2 driven immune response* They are only weak phagocytes and predominantly exert their effect by endocytosis of vesicular material* They are able to attach to the larval parasite surface in the presence of antibody or complement proteins* They help to kill larvae by: * Release of hydrolytic enxymes (from their granules / lysosomes) * Production of reactive oxygen species * Releasing major basic protein from their granules

Question 174

Briefly describe the role of mast cells and basophils in the development of an IgE mediated allergic response

Answer 174

• Allergens and antigens can stimulate the production of IgE by B cells and activated plasma cells * This production requires activation or exposure to the allergen, such that there is time for this response* IgE can then bind to F_ceRI receptors on the mast cell * This IgE binding essentiall primes the mast cell to react to the antigen specific for that IgE production* If the same antigen presents again it can bind directly with the IgE coated mast cell * Binding of antigen allows for activation of the mast cell and release of granules via exocytosis* The substances released include histamine, bradykinin, serotonin, heparin, leukotrienes and lysosomal enzymes * ​These substances mediate the majority of the clinical manifestations of an allergic response * Vasodilation, localised swelling (increased vascular permeability, pain (bradykinin mediated), increased heat etc.

Question 175

Describe the major components of the innate immune system

Answer 175

1. Phagocytosis * neutrophils and macrophages have the ability to engulf, digest and destroy invading bacteria etc2. Digestion * Destruction of ingested organisms by the acid environment of the stomach and other digestive enzymes3. Barrier * The skin prevents invasion directly4. Chemical systems and cells within the blood * Lysosyme - can attack and dissolve bacteria * basic polypeptides - can interact and inactivate certain types of gram-positive bacteria * Complement * Natural killer lymphocytes - can identify and destroy foreign cells, tumour cells and infected cells

Question 176

Describe the basic components of the adaptive immune system

Answer 176

• The adaptive immune response is generated in response to antigens from a foreign toxin or organism​ * This response is highly specific and targeted* Humoral immune response * The production of antibodies by B-lymphocytes * Antibodies are specific for a partigular antigen or allergen* Cell-mediated immunity * Development of activated T-lymphocytes that can specifically target a foreign agent

Question 177

Describe briefly the role of macrophages in the development of the adaptive immune response

Answer 177

• Tissue macrophages are primarily responsible for sampling and presentation of antigens to the B- and T-lymphocytes* The macrophages phagocytose and partially digest the invading pathogen / antigen (in phagolysosomes)* The antigen products are then liberated into the cytosol* They are then combined with antigen presenting proteins (eg. MHC II - activate T lymphocytes)* The antigens are moved the the cell surface of the macrophage (or endothelial cell) to present to or contact the local lymphocytes* Macrophages also produce IL-1 - promotes growth and division of the activated lymphocytes

Question 178

Describe briefly the role of T cells in the development of humoral immunity

Answer 178

• Humoral immunity is provided by the development of antibodies by activated B lymphocytes and plasma cells* Antigen is presented to both T and B lymphocytes.* Presentation of the same antigen to these lymphocytes causes the following (one they are already primed): * B lymphocytes start to produce antibodies * T helper cells produce lymphokines * These lymphokines provide further marked stimulation to the developing B cells * Marked increase in antibody production in the presence of concurrent T-helper cell activation

Question 179

Describe the process of plasma cell differentiation and memory cell formation

Answer 179

• B lymphyocytes initially differentiate to become highly specific for a particular antigen* Once exposed to their specific antigen, the B lymphocyte with expand taking on the appearance of a lymphoblast * Some of these lymphoblasts differentiate to form plasma blasts* The RER in the plasmablast expands rapidly and the cells divide each ~ 10 hours * Each plasmablast will divide ~ 9 times to form ~ 500 cells in less than 4 days* The lymphoblasts will also divide and mature to form clones of the originally stimulated lymphocyte - memory cells * Thus, increased numbers of specific lymphocytes are produced to migrate around the body

Question 180

Descirbe the role of memory cells in the development of a stong antibody response

Answer 180

• The initial exposure to an antigen will result in the development of a primary immune response* This primary response results in clonal expansion of the specific B lymphocyte for the specific antigen* These clonal lymphocytes are called memory cells* With a second exposure to the same antigen, there are vastly increased numbers of the specific B lymphocyte clone for expansion and differentiation into antibody producing plasma cells* This response is utilised by vaccination programs that require a second injection of antigen for development of a strong and sustained immune response

Question 181

All immunoglobulins contain both heavy and light polypeptide chains with a variable and constant portion.Describe the functional characteristics of the vairable and constant portions of the immunoglobulins

Answer 181

Variable Portion:* The variable portion is the segment that is different for each specific antigen type.* The binding of antigen occurs within the variable portion of each Ig_Constant Portion:_* This portion of the antibody conveys distinctive properties and is similar accross all antibodies of a given class * eg. IgE, IgA, IgG, IgM, IgD* This region conveys properties such as: * Diffusion within tissues * Adhesion to specific structures * Attachment to complement * Membrane diffusion properties

Question 182

Describe the 4 main direct actions that enable of antibodies to neutralise invading pathogens

Answer 182

1. Agglutination * multiple large particles are bound together in a clump2. Precipitation * Molecular complex of soluble antigen (eg. tetanus toxin) becomes so large that it is rendered insoluble3. Neutralisation * Antibodies cover the toxic site of the agent4. Lysis * Some potent antibodies can directly attack and rupture the cell membrane on pathogens

Question 183

Describe the components and primary action of the complement system

Answer 183

• The complement system is a complex of ~20 proteins, most of which are enzyme precursors* The proteins of the complement system are a normally present within the plasma* The principle protines are designated C1-C9, B and D.* The role of the complement system is to enhance the actions of antibodies and phagocytic cells in destroying pathogen, removing damaged cells from the body and promoting inflammation

Question 184

Describe the basic pathway to activation of the complement system

Answer 184

• Initiation begins following binding of an antibody to its target antigen* Antigen binding uncovers a reactive site on the constant portion of the antibody* This reactive site / activated site then directly binds with the C1 molecule of the complement system* This binding activates the proenzyme C1, setting into motion the cascade of reactions of the complement system

Question 185

Note the end effects of the various end products produced by activation of the complement system

Answer 185

1. Opsinisation and phagocytosis * C3b strongly activates phagocytosis of the bacteria to which the antibody-antigen complex is adhered2. Lysis * C5b6789 - a combination of complement proteins is called the membrane attack complex * This product inserts itself into the lipid bilayer and creates pores that allow ion transfer * Leads to osmotic rupture of the cells3. Agglutination * Alteration of the invading cell surface occurs such that they adhere to one another4. Neutralisation * Direct damage to virulence components of invading viruses5. Chemotaxis * Factor 5a is a strong chemotactic factor for neutrophils and macrophages6. Activation of mast cells and basophils * C3a, C4a, C5a all activate mast cells and basophils * Stimulates granule release - strong mediators of the inflammatory response7. Inflammatory effects * Directed inflammatory effects occur over and above that generated by mast cells and basophils * Enhanced vasodilation * Enhanced capillary permeability * Interstitial fluid coagulation

Question 186

List the three major groups of T cells

Answer 186

1. T helper cells (CD4⁺)2. Cytotoxic T cells (CD8⁺)3. Regulatory T cells

Question 187

List and describe the major actions of the T helper cells on the other components of the immune system

Answer 187

The produced lymphokines essentially regulate the remainder of the immune system1. Stimulation of growth and proliferation of the cytotoxic and regulatory T cells * Predominantly regulated by IL-22. Stimulation of B cell growth and differentiation to form plasma cells and antibodies * IL-4, IL-5, IL-6 - such a strong effect they have been called B cell stimulating factors3. Activation of the macrophage system * The lymphokines help to stop/slow the migration of macrophages once they have reached the target * They activate the macrophages for more efficient phagocytosis4. Positive feedback onto the T-helper cells * Especially IL-2 - direct positive feedback effect on stimulation of the T-helper cells

Question 188

Briefly describe the mechanism of action of the cytotoxic T cells

Answer 188

• The receptor proteins expressed by cytotoxic T cells allow them to bind avidly to specific organisms or cells* After binding they secrete proteins called perforins * ​Perforins punch round holes in the cells membranes allowing easy passage of ions and fluid into the cell* The cytotoxic T cell also secretes cytotoxic substances directly into the attacked cell/organism* The T cells can then detach from the attacked cell and move to another* They are especially lethal to viral infected cells and also play an important role in the destruction of neoplastic cells

Question 189

Describe the major role of the T regulatory cells

Answer 189

• While their role not fully ellucidated, they predominantly suppress the immune response* By supressing or regulating the effects of the T helper cells and the cytotoxic T cells, they can limit the potential damage caused by an activated immune system* They play a major role in limiting the ability of the immune system to attack self antigen* Largely responsible for immune tolerance

Question 190

List the contents of the platelets and note the major function of each product

Answer 190

1. Actin and myosin molecules and thrombosthenin * Enable platelets to contract2. ER and golgi residues * Synthesise the enzymes and proteins * Storage of calcium ions3. Mitochondria * Energy generation4. Enzyme systems5. Fibrin-stabilising factor - FXIII * Enzyme responsible for the formation of fibrin crosslinks6. Vascular endothelial growth factor (VEGF) * Stimulates endothelial and smooth muscle cells together with fibroblasts - help repair damaged endothelium

Question 191

Describe the processes that occur during the formation of a normal platelet plug

Answer 191

• Exposure of the subendothelial collagen is the initial stimulation for platelet plug formation - ie. from vascular damage* The platelets swell and develop numerous pseudopods * The cell surface becomes more adhesive* Cell surface Gp1b receptors bind to vWF attached to the subendothelial collagen* The contractile elements in the platelets activate and granules are released * ADP and platelet activating factor (PAF) * Thromboxane is produced* More platelets are recruited and adhere to the original activated platelets

Question 192

Describe the production, metabolism and action of prothrombin

Answer 192

• Continually produced in the liver* 68.8 kDa in size (similar to albumin)* Can be cleaved by extrinsic or intrinsic tenase (FVII+TF, FXa+FVIII) * Prothrombin is split to liberate thrombin* Prothrombin is being continually used and there are no significant body stores * Halted production as with acute liver insufficiency will lead to low blood levels within ~1 day* Prothrombin cleavage and activation is vitamin K dependent* Thrombin, produced rapidly during coagluation, catalyses cleavage of 4 peptides from each fibrinogen molecule * This allows the individual fibrinogen monomers to polymerise to for long fibrin fibres

Question 193

Briefly describe the process of clot retraction

Answer 193

• A blood clot is a cluster of platelets, red and white blood cells together with plasma.* The blood clot is held together by an extensive network of fibrin strands that are cross-linked by the action of Factor XIIIa (released by the platelets - and activated by thrombin)* Within minutes of clot formation, contraction of platelet elements helps to extrude the excess fluid - serum* Platelet contractile elements are responsible for the contraction * Actin, myosin and thrombosthenin * Require calcium which is released from the golgi, ER and mitochondria* Tight adhesions between the platelets, fibrin and the underlying subendothelial tissues help to bring the damaged vascular endothelium together* Retraction also enables strengthening of the clot and the meshwork becomes more dense

Question 194

Describe the factors that prevent blotting in a normal vascular system

Answer 194

• Smooth endothelial surface prevents contact activation * Subendothelial collage and vWF remain hidden* Glycocalyx - mucopolysaccharide layer adsorbed to the endothelial cells * repels clotting factors and platelets preventing their activation* Thrombomodulin * Bound within the endothelial membrane - binds and removes thrombin* Thrombin-thrombomodulin complex * Activates Protein C * Protein C inactivates FV and FVIII* ​Production of PGI₂ (prostacyclin) and NO by endothelial cells​ * Both inhibit platelet aggregation and cause vasodilation

Question 195

Describe the action of the major anticoagulats within the blood

Answer 195

1. Antithrombin III circulates within the blood * ATIII initially blocks the action of thrombin on fibrinogen * Secondarily inactivates the thrombin2. The fibrin formed during the coagulation process * The majority of thrombin formed in adsorbed within the developing fibrin matrix * This process ensures that the majority of the thrombin formed during coagulation remains local and prevents excessive spread of the clot.

Question 196

Describe how endogenous heparin contributes to the anticoagulation balance within the body

Answer 196

• Heparin is produced and stored within basophils and mast cells predominantly * Heparin is continually produced and released * It is present in the largest quantities in the basophilic mast cells in the precapillary connective tissue * Especially within the lungs and liver* Heparin by itself has minimal anti-coagulant properties and remains in low concentration within the body* Heparin acts by markedly increasing the activity of antithrombin III (ATIII)* ATIII+heparin removes: * Thrombin * FIX through FXII* Heparin therefore reduces the concentrations of some of the activated coagulation factors and thrombin.* Heparin is contstantly produced to ensure minimal growth of the tiny clots formed continually within the body

Question 197

Describe the activation of plasmin and its mechanism of action

Answer 197

• Plasmin circulates in the blood in the inactive state called plasminogen* Plasminogen is bound within newly formed blood clots* Damaged tissue including the vascular endothelium very slowly release tissue plasminogen activator (t-PA) which slowly converts plasminogen to plasmin within a few days of clot initiation* Plasmin is a proteolytic enzyme with a similar structure to trypsin* Plasmin digests fibrin fibres helping to remove the formed clots * This process can re-establish blood flow within the tiny capillaries which would otherwise be occluded by the clot* Plasmin also digests / inactivates fibrinogen, FII, FV, FVIII, FXII * This helps to minimise clot formation and can cause localised hypocoagulability

Question 198

Describe the nervous system control within the bronchiolar network

Answer 198

• The bronchiolar wall are almost entirely composed of smooth muscle cells* The smooth muscle cells are innervated by both the sympathetic nervous system and the parasympathetic nervous system * Bronchiolar smooth muscle cells predominantly express beta adrenergic receptors together with muscarinic cholinergic receptors* There is minimal direct sympathetic neural stimulation of the bronchioles * The sympathetic nervous system predominantly acts through the neurotrasmitters NE and epinephrine produced by the adrenal medulla* Epinephrine as a potent stimulator of beta adrenergic receptors (moreso than NE) causes bronchiolar relaxation and dilatation* Vagal nerve parasympathetic fibres innervate the bronchioles and cause smooth muscle constriction via the action of ACh * Vagal stimulation may also be elicited locally primarily following irritation to the epithelial membrane

Question 199

Describe the basic production and role of the mucus layer in the respiratory passageways

Answer 199

• Mucus is produced and secreted by the respiratory goblet cells and by small submucosal glands * Mucus is 97% water, 3% solid * Mucins are large glycoproteins that are strongly anionic - these comprise ~ 30% of the solids * Mucin provide vast numbers of binding sites for pathogens which are then trapped * The mucins effectively regulate the water content of the mucus* The mucus serves to: * Minimise dehydration * Trap small particles * Lubricate the airways

Question 200

Describe the cough reflex and its function

Answer 200

• The cough reflex is triggered by irritation to the respiratory epithelial lining, especially at the larynx and carina * Chemical stimuli within the deeper airways can elicit a cough reflex also* The initial stimulus triggers nerve conduction by the vagus nerve to the medulla triggering an automatic response1. Initial rapid inspiration2. Epiglottis and vocal cord closure3. Abdominal and intercostal muscle contraction * Increased pressure within the airways to as much as 100 mmHg * Causes collpase of the smaller airways increasing the shear force of the air movement during expulsion4. Sudden opening of the vocal cords and epiglottis * Allows for rapid expulsion of air carrying mucoid secretions and trapped particles to the pharynx and out through the mouth

Question 201

Describe the sneeze reflex and its function

Answer 201

• The sneeze reflex is initiated by irritation to the nasal mucosa* The afferent impulse is transmitted through the trigeminal nerve to the medulla* The triggered reflex is automatic* Initially, there is a rapid inspiratory effort* The uvula is depressed and the back of the tongue elevates, partially closing off the oral cavity* Air is then forcefully expelled through the nose* The forceful expulsion carries with it secretions and irritants that are present within the nasal cavity.

Question 202

Briefly describe the components of the pulmonary circulation

Answer 202

• Pulmonary artery * The PA branches to supply left and right lungs * The branches are short - ie. rapidly branch * The arterial walls are thin and significantly more distensible than systemic arteries * This provides a large compliance to accomodate the RV stroke volume* Pulmonary veins * Similarly short and rapidly join to form the pulmonary vein which empties immediately into the left atrium* Bronchial vessels * Blood flows to the lungs through the bronchial arteries that originate from the systemic circulation * This blood is oxygenated and supplies the bronchi together with the supporting tissues with oxygen * The bronchial vessels empty into the pulmonary veins and left atrium* Lymphatics * Present in all of the connective tissue * Course through the interstitium towards the hilus where they (mainly) join the right thoracic duct * The lymphatic ducts drain into the large veins and then the left atrium

Question 203

Describe the effects of reduced local alveolar oxygen content on local pulmonary vascular blood flow

Answer 203

• Reduced oxygen content within the alveolus causes the adjacent blood vessels to constrict * ​This is the opposite of the effect in the systemic circulation where autoregulation causes vasodilation* Low oxygen tension may do the following: * Promote the release of endothelin or reactive oxygen species * Increase the local tissue sensitivity to endothelin * Decrease the release of nitric oxide, a potent vasodilator * Inhibit oxygen-sensitive potassium channels in the vascular smooth muscle leading to depolarisation, calcium influx and contraction/constriction

Question 204

Why is it important that the pulmonary vasculature constricts in response to low oxygen tension in the alveoli?

Answer 204

• Constriction of the small arterioles leads to an increased vascular resistance and reduced blood flow within the capillaries* This serves two distinct benefits: * The reduced blood volume moves mores slowly through the capillary bed, thus absorbing more oxygen * The blood is shunted to areas with less resistance and higher oxygen content* This mechanism helps to ensure that the blood flow is distributed proportionally to the areas that are well oxygenated

Question 205

Describe how the pulmonary blood flow changes during periods of high need (eg. exercise). Explain his these changes help with respect to cardiac function

Answer 205

• With increased exercise or oxygen demand (increased cardiac output), there are multiple changes that occur: * There is an initial increase in pulmonary arterial pressure * There is almost instantaneous opening of tiny capillaries (up to three-fold in humans) that are normally closed * All capillaries dilate * These two processes effect a decrease in pulmonary vascular resistance* The increased capacitance of the pulmonary vasculature offsets the increases in pulmonary arterial pressure that would otherwise be required to ensure adequate oxygen transport * This effect is protective to the right side of the heart, minimising any increased work and conserving energy* These effects also help to minimise any change in the rate of blood flow through the alveoli (though the speed of blood flow through the capillary does increase nearly 3 fold) - this helps to maintain adequate oxygenation of haemoglobin

Question 206

Describe the changes that occur in the pulmonary circulation as left atrial pressures increase

Answer 206

• Left atrial pressures increase with progression of left sided heart failure * This progression can be due to reduced systolic function (reduced ejection fraction) or increased regurgitation (increases end diastolic volume)* Normal left atrial pressure is 1-5 mmHg * Increases start to be transmitted to the pulmonary circulation when the pressure reaches >7-8 mmHg* Increases in left atrial pressure are transmitted to the pulmonary veins, capillaries and ultimately the pulmonary artery almost equally* Therefore, increased left atrial pressure causes a direct increase in the pulmonary artery pressure and work load of the right ventricle during systole* As the left atrial pressure rises > 30 mmHg (in humans), the capillary hydrostatic pressure increases such that pulmonary oedema can occur * At this pressure, the increased leak of fluid into the interstitium outstrips the rate at which lymphatics can return the fluid to the systemic circulation.

Question 207

Briefly describe the pulmonary interstital fluid dynamics and contrast that of the systemic ciculation

Answer 207

• Fluid leaks from the vascular spaces into the interstitum based on Starling’s laws * Outward forces * Vascular (capillary) hydrostatic pressure * Interstital colloid pressure * Lymphatic drainage / negative interstital fluid pressure * Inward forces (into the vasculature) * Vascular colloid pressure* The capillary hydrostatic pressure is ~ 7 mmHg, much lower than the systemic hydrostatic pressure* The interstital colloid pressure is ~ twice that of the systemic interstitum at 14 mmHg* The negative interstital fluid pressure is greater than the systemic interstitium at - 8 mmHg* The combination of outward forces equals ~ 29 mmHg* The plasma oncotic pressure is ~ 28 mmHgThe net effect is slow production of pulmonary interstital fluid due to a small mean filtration pressure of ~ +1 mmHg

Question 208

Describe how the formation of pulmonary oedema varies in the acute versus the chronic setting

Answer 208

• Pulmonary oedema will form when the capillary hydrostatic pressure increases above that of the plasma oncotic pressure * There is a limited ability for the vasculature and lymphatics to accomodate increases in hdrostatic pressure from 7 mmHg to ~ 28 mmHg* If there is an acute increase in left atrial pressure as may occur with rupture of a chordae tendinae due to mitral valve endocardiosis, sudden increases in LA pressure lead to sudden increases in capillary hydrostatic pressure and oedema formation* With chronic slowly increasing elevations in pulmonary pressures due to slowly progressive heart disease, compensatory mechanisms have time to develop. * The left atrium will dilate * The vascular capacitance increases * Lymphatic vessels expand up to 10-fold to ensure more rapid fluid drainage* Left atrial and capillary hydrostatic pressures can increase to ~ 40-45 mmHg before the development of pulmonary oedema

Question 209

Describe the structure of the respiratory membrane

Answer 209

• The respiratory membrance comprises all membranes of the respiratory system through which gas exchange occurs * This includes the walls of the alveoli, alveolar ducts and terminal bronchioles* The membrane consists of the following: * Fluid layer including surfactant on the alveolar - gas interface * Alveolar epithelium - thin epithelial cells * Epithelial basement membrane * Thin layer of interstitial tissue * Capillary basement membrane * The two basement membranes fuse in many places allowing for an even thinner membrane * Capillary endothelium* The pulmonary capillaries are also tiny at ~ 5 um in diameter such that the RBCs touch the endothelial surface

Question 210

List and briefly describe the factors that can affect the rate of gas diffusion through the respiratory membrane

Answer 210

• Membrane thickness * Can be increased in disease states where there is fibrosis, oedema or cellular infiltration * Increased respiratory secretions also increase the diffusion distance and reduce the diffusion rate* Surface area of the membrane * Can be markedly reduced with emphysema, chemical injury to the alveolar epithelium (aspiration pneumonia) or following surgical lung lobectomy* Diffusion coefficient of the gas* Partial pressure difference of the gas on either side of the membrane * Increased oxygen tension in the alveolus will increase the rate of diffusion into the red blood cells * Increased CO₂ production during exercise will increase the rate of outward diffusion of CO₂ in the alveolus

Question 211

Describe the physiological causes for ventilation perfusion mismatch

Answer 211

• Ventilation perfusion mismatch occurs when the rate of oxygen delivery to the alveolar capillaries is not “matched” to the rate of oxygen delivery to the alveolar space. What ever the cause, this results in reduced gas exchange at the alveolus1. Reduced alveolar surface area * Results in inadequate blood flow to accomodate the gas transfer. * Increased physiological dead space2. Reduced blood flow to the alveolar capillary * eg. pulmonary thromboembolism * Reduced blood flow towards zero reduces gas exchange towards zero3. Increased blood flow to the alveolar capillary relative to ventilation (increased blood flow or decreased ventilation) * eg. lung torsion * Marked reduction in gas transfer and return of deoxygenated blood to the circulation * Increased physiological shunt4. Increased airflow to the alveolus * similar to 1 - increased dead space, increased CO₂ expiration and respiratory alkalosis

Question 212

List and briefly describe the various control mechanisms that exist to ensure ventilation is adequate to meet the respiratory needs of the body

Answer 212

1. Chemical control mechanisms * ​Primarily driven by increases in H⁺ * However, H⁺ does not easily cross the blood brain barrier. Therefore systemic acidosis only has a mild effect on respiration * CO₂ will readily cross the blood brain barrier * Increased CO₂ immediately reacts with water to form carbonic acid and H⁺ * Thus, H⁺ is increased in the respiratory centre much more readily by increases in CO₂2. Chemoreceptor controls * Located in the carotid and aortic bodies * Sense oxygen tension and stimulate the afferent fibres likely via ATP release. * Stimulation of the vagus nerve stimulates the respiratory centre * Also respond to increases in CO₂ and H⁺

Question 213

Define the parameters used to diagnose a respiratory acidosisProvide examples of causes of respiratory acidosis

Answer 213

• Respiratory acidosis is present when there is an increase in the CO₂ with a normal bicarbonate in the face of a reduced blood pH (< 7.35)* Respiratory acidosis occurs when there is a primary failure of oxygen and carbon dioxide transport in the lungs and hypoventilation * Primary pulmnonary parenchymal disease - pneumonia or pulmonary fibrosis * Neuromuscular disorders - botulism, tick paralysis MG, brain stem injury * Reduced respiratory drive or reduced respiratory excursion * Airway obstruction * Central respiratory depression - sedatives, trauma, status epilepticus

Question 214

Define the parameters used to diagnose a respiratory alkalosisProvide examples of causes of respiratory alkalosis

Answer 214

• Respiratory alkalosis occurs when there is a reduction in venous CO₂ with a normal bicarbonate in the presence of an increased blood pH (> 7.45)* Respiratory alkalosis is caused by increased respiratory rate or volume without a specific physiological need (ie. without increased metabolic activity)* Respiratory alkalosis can be acute or chronic* Causes include: * High altitude and reduced oxygen tension will cause an increased respiratory drive and reduced CO₂ * Pain / anxiety * Neurological disease including vascular accident * Sepsis / fever (prior to metabolic acidosis) * Thyrotoxicosis

Question 215

Define the laboratory parameters to diagnose metabolic acidosis with respiratory compensationDescribe the mechanism of respiratory compensation in the context of metabolic acidosis

Answer 215

• Metabolic acidosis is diagnosed by the presence of a low blood pH (< 7.35) with low HCO₃^-* Initially, the CO₂ should be normal with primary metabolic acidosis* Metabolic acidosis will then stimulate an increased respiratory drive and subsequent reduction in the CO₂ * The change in CO₂ should remain less than the change in HCO₃^- as compensation is not perfect* Increased H⁺ ions ⇒ carbonic anhydrase enzyme catalyses the reaction with HCO₃^- to form CO₂ and H₂0 * Therefore acidosis results in a increased CO₂ initially * CO₂ increases stimulate the respiratory centre in the medulla to increase respiratory volume (effort and rate) * Increased respiratory effort will cause a reduction in the circulating CO₂

Question 216

Define the laboratory parameters to diagnose metabolic alkalosis with respiratory compensationDescribe the mechanism of respiratory compensation in the context of metabolic alkalosis

Answer 216

• Metabolic alkalosis is defined as an increase in the blood pH (> 7.45) in conjunction with an increase in HCO₃^- * Metabolic alkalosis primarily occurs when there is an increased loss of acid from the body * Primarily occurs with acute or chronic vomiting or with potassium wasting and hypokalaemia* A loss of acid from the body results in the accumulation of HCO₃^- * Acid loss stimulates the conversion of CO₂ and H₂0 to H⁺ and HCO₃^- via the enzymatic action of carbonic anhydrase * This helps to balance and restore the lost acid but results in an increase in HCO₃^- and decrease in CO₂* Decreased CO₂ is sensed within the medullary respiratory centre causing a reduction in respiratory volume (depth and effort)* Full compensation occurs when the pH is returned to normal * HCO₃^- and CO₂ would be increased

Question 217

Name the major components of the intracellular fluid

Answer 217

• Water* Potassium* Magnesium* Phosphate

Question 218

What are the major components of the extracellular fluid

Answer 218

• Water* Sodium* Chloride* Bicarbonate* Nutrients * Oxygen * Glucose * Amino acids * Fatty acids* Waste products * eg. carbon dioxide

Question 219

In broad terms, describe the major functions performed by the various organ systems to maintain homeostasis

Answer 219

• Lungs: * Provide oxygen to the extracellular fluid * Remove carbon dioxide* Kidneys: * Maintain ion concentrations - potassium, sodium etc * Maintain acid/base balance * Monitoring and maintenance of extracellular fluid volume * Soluble waste removal* Gastrointestinal tract * Provision and absorption of nutrients * Insoluble waste removal* Liver * Metabolism of drugs/chemicals * Excretion of wastes via the bile

Question 220

Extracellular fluid transportDiscuss the mixing of the extracellular fluid components within the blood vessels and the interstitial spaces

Answer 220

• Blood is transported through the arteries to capilliaries and back via veins to the heart* Mixing of the extracellular fluid component occurs within the capilliary beds* Capiliaries are permeable to most of the blood plasma components - except plasma proteins* Fluid and dissolved constituents move back and forth between the capiliaries and the interstitial spaces. * This movement is in large part driven by kinetic motion of the molecules* Capiliaries are in close contact with almost all cells in the body * Thus diffusion of almost any substance can occur within seconds* This diffusion ensures constant mixing and homogeneity of the intravascular and extravascular extra-cellular fluid.

Question 221

Regulation of Body FunctionsDescribe the major components of the nervous system and how they contribute to homeostasis maintenance

Answer 221

• Sensory input, central NS (integrative), motor output* Autonomic Nervous SystemSensory:* Receptors in the skin and the special sensory organs monitor the surrounding environmentCNS:* Integrates sensory inputs* Stores information* Generates thoughts and creates ambition* Determines reactions in response to various sensationsMotor:* Performs the movements as determined or desired by the CNS* Localised reactive movements are also performedAutonomic:* Operates at a subconscious level* Controls the function of internal organs including the heart, GIT and secretion from the various glands

Question 222

List various hormone systems and their effect on homeostasis

Answer 222

1. Thyroid * Regulates cellular metabolism - rate of chemical reactions2. Insulin * Regulates glucose metabolism and helps maintain glucose homeostasis3. Adrenocortical hormones * Aldosterone: Regulate sodium and potassium balance * Cortisol: regulates protein metabolism4. Parathyroid hormone * Tightly regulates blood calcium and phosphate

Question 223

What are the major components of the immune systemHow does the immune system contribute to maintenance of homeostasis

Answer 223

• White blood cells* Tissue cells derived from white blood cells* Thymus* Lymph nodes* LymphaticsThe immune system provides a mechanism to:1. Distinguish self and foreign (and potentially harmful) substances2. Destroy, neutralise or remove foreign substances

Question 224

How does the integumentary system contribute to homeostasis?

Answer 224

• Protection of the body from the outside world* Water balance - primarily preventioni of water loss* Regulation of body temperature * Sweating to assist with cooling * Air-trapping to help limit temperature loss / regulate the skin surface environment* Can contribute to waste excretion

Question 225

Discuss the basic control mechanism of oxygen levels in the extracellular fluid

Answer 225

• Oxygen concnetration in the ECF largely relies on the composition and characteristics of haemoglobin* Haemoglbin has a high affinity for oxygen* Hb combines with oxygen within the lungs * The heart serves to pump both de-oxygenated and oxygenated blood around the body* Hb releases oxygen in the capiliary beds and into the tissue fluid when there is low oxygen concentration * The oxygen passes along a diffusion gradient determined largely by the metabolic rate of the tissue * Diffusion alone does not account for the degree of oxygen transport into the tissue bed * The tissue bed serves as an oxygen sink * Oxygen diffuses through arteriolar and venule walls as well as at the level of the capillary.

Question 226

Briefly describe the control mechanisms to ensure carbon dioxide homeostasis and removal.

Answer 226

• Carbon dioxide is a major end-product of oxidative reactions within cells* Carbon dioxide readily diffuses from the tissue extracellular fluid into the plasma* Increased CO2 in the plasma activates the respiratory centre * Increases respiration effort and tidal volume* CO2 diffuses into the alveolar spaces within the lungs down a diffusion gradient.* Respiratory efforts expel excessive carbon dioxide into the environment.

Question 227

Describe the baroreceptor reflex and how it serves to regular arterial blood pressure.

Answer 227

• Barorecptors are specialised nerve receptors that respond to arterial wall stretch* Baroreceptors are located in the carotid arteries and the aortic trunk* With increased arterial pressure, there is increased baroreceptor stimulation * Increased nerve impulses are transmitted to the vasomotor centre of the medulla oblongata * Increased inputs leads to a decrease in the number of impulses transmitted to the sympathetic nervous system * Reduced SNS activation leads to a reduced heart rate and peripheral vasodilation* Conversely, reduced blood pressure leads to reduced stimulation of the baroreceptors, reduced inhibition of the vasomotor centre and increased stimulation of the SNS

Question 228

Describe the nature of homeostatic control systems

Answer 228

• The majority of control systems act by negative feeback * Eg. high carbone diaxoide concentration leads to increased respiration with an end goal of reducing carbon dioxide - a result negative to the initial abnormality within the system* Negative feedback acts to return a parameter towards normal when it becomes either deficient or excessive* The degree to which a control system operates is referred to as the gain * ​The gain refers to the ability of the body system to correct for an error (Gain = correction/error)

Question 229

Describe and provide examples of positive feedback mechanisms

Answer 229

• Positive feedback occurs when the inciting stimulus contributes to more of the original stimulus. * A damaged blood vessel initiates the coagulation cascade. Stimulation of the local clotting factors causes amplification of the clotting process and further activation of local coagulation enzymes / proteins. * Generation of a nerve signal: stimulation causes slight sodium leagage into the nerve cell. This alters the cell memprane potential and further sodium channels are opened and further sodium influx. This creates an action potential which generates an electrical current. This current initiates additional action potentials in adjacent nerves

Question 230

Describe the basic cell structure

Answer 230

• Nucleus and cytoplasm are the two major components* The nucleus is surrounded by the nuclear membrane* The cytoplasm is contained by the cell membrane (or plasma membrane)* The cell is made up of different substances collectively called the protoplasm* The protoplasm contains * Water * Electrolytes * Proteins * Lipids * Carbohydrates

Question 231

Describe the components and basic structure of the cell membraneDescribe the major functions of the various components of the cell membrane

Answer 231

• 55% protein, 25% phospholipid, 13% cholesterol, 4% other lipids, 3% carbohydrates* Phospholipid bilayer with hydrophoic ends attached to each other centrally, hydrophilic ends contact the intra- and extra-cellular fluid* Cholesterol molecules are essentially dissolved within the bilayer. * Cholesterol composition largely controls the degree of permeability/impermeability to water soluble components. * Cholesterol controls the fluidity of the cell membrane* Integral (trans-membrane) and Peripheral cell membrane proteins * Integral proteins provide pores through which water and water-soluble substances can diffuse * Also can act as carrier proteins for active transport against the diffusion gradient * Integreal proteins can act as receptors for water-soluble peptides / hormones which acan then activate secondary messengers within the cell. * Peripheral cell membrane proteins function almost exclusively as enzymes that alter transport of substances through the pores

Question 232

Describe the structure and role of cell membrane carbohydrates

Answer 232

Structures:* The majority of cell membrane carbohydrates are in the form of glycoproteins or glycolipds* Proteoglycans are mainly carbohydrates bound to small proteins * These are attached loosely to the cell surface* The outer surface of the cell has a “loose’ carbohydrate coat called the glycocalyx_Functions:_1. Negative electrical charge to repel adjacent cells / objects2. Glycocalyx attached to adjacent glycocalyx - cell to cell adhesion3. Many carbohydrates act as receptors4. Some carbohydrates are important for immune reactions

Question 233

Describe the various processes by which nutrients and molecules can move into a cell.

Answer 233

• Passive Diffusion * Lipids move directly through the membrane * Many electrolytes pass through “pores” that may require activation or only allow certain molecules throughActive transport* Pinocytosis - tiny vesicles that engulf most large macromolecules. Eg. most proteins. Form in coated pits on the cell surface* Phagocytosis - large vesicles form to engulf larger particles. Only certain cells have the ability to perform phagocytosis. Eg. Macrophages, neutrophils.

Question 234

Describe the process of phagocytosis

Answer 234

• Bacterium or particle is opsinized by antibodies* Antibodies bind to receptors on the phagocyte cell surface* Membrane edges surrounding the particle evaginate to surround the particle* More and more membrane receptors attach to the particle ligands - “zipper like” motion* Actin and contractile elements in the cytoplasm contract pushing the vesicle inwards* Contractile proteins pinch off the stalk leaving the phagocytic vesicle free within the cytoplasm

Question 235

Descirbe the process by which the contents of an endocytotic vesicle is digested

Answer 235

• Pinocytosis or phagocytosis results in the formation of an intra-cytoplasmic vesicle.* Almost immediately, lysosomes attach to the vesicle surface* Hydrolases are released into the vesicle* Hydrolases break down the components of the vesicle * Hydrolysis of proteins, carbohydrates and lipids results in the products of digestion * glucose, amino acids, phosphates* Digestion products can then diffuse through the vesicle membrane into the cytoplasm* The residual body represents the indigestible substances - released from the cell via exocytosis

Question 236

Note the action of lysosomes in the presence of cell damage

Answer 236

• When a cell is damaged (heat, cold, trauma, chemicals) lysosomes can rupture* The ruptured lysosome releases hydrolases into the cytoplasm directly which starts the process of cell digestion* If there is minor damage, small numbers of lysosomes are damages only and cell repair can ensue.* If there is major damage and many lysosomes are ruptured, autolysis of the cell occurs

Question 237

What three bactericidal agents are contained within lysosomes?Briefly note the role of each

Answer 237

1. Lysozyme * Dissolves the cell wall2. Lysoferrin * Binds iron and other substances necessary for bacterial growth3. Acid pH of ~5.0 * Activates hydrolases * Inactivates bacterial metabolic systems

Question 238

Descirbe the processes that occur within the endoplasmic reticulum

Answer 238

• Protein is synthesised in the rough ER* Lipids and cholesterol are synthesised in the smooth ER * rapidly incorporated into the smooth ER lipid bilayer * vesciles continually break off and migrate to the golgi apparatus* Provides the enzymes for glycogen breakdown* Provision of a vast number of enzymes capable of detoxification * coagulation, oxidation, hydrolysis and conjugation with glucuronic acid

Question 239

Describe the processes and functions of the golgi apparatus

Answer 239

• Further processing of substances already formed in the ER* Carbohydrate moeities are added to the formed proteins* The ER secretions are concentrated and packaged into secretory vesicles* Synthesis of certain carbohydrates * large polysaccharide polymers bound with small amounts of protein such as hyaluronic acid and chondroitin sulfate

Question 240

Broad strokes of the citric acid cycle

Answer 240

• Glucose, fatty acids and amino acids are taken into the cell.* Pyruvic acid from glucose and acetoacetic acid from FA and AA * Both eventually converted into acetyl CoA* Acetyl CoA enters the citric acid cycle * Acetyl CoA is split into component parts - hydrogen atoms and carbon dioxide * Carbon dioxide diffuses out of the cell * Hydrogen atoms are converted to hydrogen ions * H ions combine with oxygen to release energy* ADP is converted to ATP and H combines with oxygen to produce water.

Question 241

What are the three major categories of cellular function that utilse ATP

Answer 241

1. Transport of substances through membranes2. Synthesis of chemical compounds3. Mechanical work

Question 242

Briefly list the events that allow cellular ameboid movement

Answer 242

• A pseudopodium protrudes from one end of the cell.* Pseudopodium partially attaches to new tissue area* New cell membrane is formed at the pseudopodium by attachment release of exocytic vesicles* Old cell membrane is recycled and receptors disengaged by the formation of endocytic vesicles at the “tail” end* Ecocytic vesicles can contain receptors that bind to the adjacent tissue* Actin is present within the cytoplasm and forms a filamentous network.* Actin binds with myosin and contraction of the filaments can occur* Chemotaxis is the major means of control of ameboid movement.* Chemical mediators cause membrane changes leading to the development of pseudopodia

Question 243

List the cells that exhibit ameboid movement

Answer 243

1. While blood cells - to migrate out of blood vessels * Neutrophils * macrophages2. Fibroblasts * to migrate and move to areas of damage3. Embryonic cells * migration occurs during foetal growth4. Cancer cells * Especially sarcomas * Major mechanism for progression to metastasis.

Question 244

What are the major locations of cilia within the body?What is the structure and function of the cilia?

Answer 244

1. Cilia are location primarily within the respiratory tract and fallopian tubes* Cilia are composed of 11 microtubes - 9 in pairs around the outside and 2 single tubules centrally. These tubules are supported and bound together by a complex of protein cross links* Cilia function by beating in a co-ordinated whip like motion to move fluid on the cell surface * Towards the pharynx in the respiratory tract and towards the uterine body in the female reproductive tract

Question 245

Describe the knows aspects of ciliary movement

Answer 245

1. The microtubules are all linked together by protein cross links - the structure is called the axoneme2. Cilia can still function without the cell membrane3. ATP must be available for function4. Appropriate ionic conditions must exist * Especially calcium and magnesium5. Mictotubes on the front edge of the cilium crawl out / slide towards the cilia tip causing bending6. Multiple protein arms composed of dynein project from each double tubule * These dynein arms have ATPase enzyme activity7. The central cilia may be responsible for an electrochemical signal - when not present, cilia do not beat

Question 246

Discuss the structure and action of primary (sensory) cilia

Answer 246

• Primary cilia are non-motile and generally solitary on each cell* They are thought to act as a sensory antennae * Sense chemical and mechanical signals* Transduction of sensory signals to initiate multiple cellular effects. * May be driven in part by changes in intra-cellular calcium signalling* Defects in signalling by primary cilia in renal tubular cells is thought to contribute to polycystic kidney disease

Question 247

What are the basic DNA building blocks

Answer 247

1. deoxyribose2. Phosphoric acid3. Nitrogenous bases * guanine * cytosine * adenine * thymine4. Weak hydrogen bonds between bases hold the two strands together

Question 248

What are the RNA building blocks?

Answer 248

• Ribose* Phosphoric acid* Nucleic acids * Pyrimidines * Uracil and cytosine * Purines * Guanine and adenine* Weak hydrogen bonds

Question 249

Briefly describe the process of transcription

Answer 249

• RNA polymerase attaches to a promoter sequence of DNA nucleotides* Attaching of RNA polymerase leads to unwinding of ~ 2 coils of the DNA* New activated RNA nucleotides are added as RNA polymerase moves along the single DNA strand* RNA polymerase breaks away phosphate radicals from the RNA nucleotides to liberate energy * This energy is used to form a bond between the remaining phosphate at adjacent ribose* Weak hydrogen bonds are formed between the DNA strand and forming RNA* RNA elongation continues until RNA polymerase encounters a STOP codon (chain-terminating sequence)* Weak hydrogen RNA-DNA bond breaks as the DNA-DNA bond has a greater affinity* RNA is released into the cytoplasm

Question 250

Briefly describe the process of translation

Answer 250

• mRNA moves from the nucleus through the cytoplasm to the ribosomes on the rough endoplasmic reticulum* The mRNA moves through the ribosome with each codon encoding for a specific amino acid.* Transfer RNA (tRNA) transports the amino acids to the ribosome for addition into protein molecules* Chemical reactions take place within the ribosome to bond the growing amino acid chain into a single protein molecule* A STOP codon passing through the ribosome signals the end of the protein molecule and it is freed into the cytoplasm

Question 251

Briefly note the components of gene expression

Answer 251

1. The specific sequence of the individual DNA2. Information from the DNA is used to produce vast arrays of RNA * RNA has numerous forms that may promote (mRNA), assist (tRNA) or regulate (miRNA) protein synthesis3. The over-arching process of RNA and protein synthesis is referred to as gene expression4. The process of gene expression directly affects the phenotype as its final effect

Question 252

List the various control mechanisms that modulate and regulate gene expression

Answer 252

1. Basal promoter (TATAAA bases - TATA box) * Binding of RNA polymerase is necessary for initiation of transcription2. Upstream promoter * Several binding sites for both positive and negative transcription factors3. Enhancers * Regions of DNA that can bind transcription factors * May be remote from the gene they act on - even on a different chromosome4. Insulators * Gene sequences that provide a barrier against transcriptional influences from surrounding genes5. Control points exist apart from RNA transcription also * RNA processing can be regulated * Translation by the ribosaome can be influenced * Enzymes can influence many levels of gene expression6. Transcription factors can control the DNA structure thus making it available or unavailable for transcription to occur

Question 253

Briefly describe the mechanism and role of enzyme regulation on gene expression

Answer 253

1. Enzyme inhibition * The synthesised enzyme (almost always) binds back with the first enzyme in a sequence, blocking activity * Intermediary enzymes thus do not build up * An example of negative feedback * This mechanism helps control intracellular concentrations of multiple amino acids, purines, pyrimidines, vitamins and other substances2. Enzyme activation * Normally inactive enzymes are activated in certain circumstanses * eg. cAMP (produced by ATP breakdown) increases cause activation of the glycogen splitting enzyme phosphorylase - leads to gluocse molecule liberation for energy generation and increase of ATP stores

Question 254

List the steps in DNA replication

Answer 254

• DNA helicase starts to “un-zip” and a replication fork is formed* RNA primers attached to the 3’ end of the leading strand* DNA polymerase binds to the leading strand and creates a new strand via elongation * This strand is continuous* Multiple primers attach to the 5’ (lagging strand) which are several bases apart* DNA polymerase then adds pieces of DNA called Okazaki fragments** DNA ligase joins the Okazaki fragments to form a continuous strand Exonuclease removes the RNA primers* Another exonuclease “proofreads” the DNA

Question 255

List the phases of mitosis

Answer 255

​Mitosis commences AFTER chromosomal duplication has occurred* Prophase * Chromosomes become condensed into well defined strands* Prometaphase * Multiple microtubules from the aster attach to the chromatids at the centromere * Tubules then pull one chromatid of each pair to each pole of the cell* Metaphase * The two asters are pushed farther apart * The chromatids are pulled tightly to the cell centre to form the equatorial plate* Anaphase * The two sets of chromatids are pulled apart toward each mitotic aster* Telophase * Mitotic apparatus dissipates * New nuclear membrane forms from endoplasmic reticulum * Cell pinches in two via contraction of a ring of microfilaments

Question 256

Note the mechanisms by which cell growth can be regulated and controlled

Answer 256

1. Growth factors * Derived from somewhere remote from the cell/tissue * Can be derived from adjacent connective tissue or a hormone derived from a remote organ2. Growth stops when the cells have run out of space for growth3. Cell secretions (own cells) can inhibit cell growth * negative feedback control

Question 257

What are proto-oncogenes?How may they contribute to the development of cancer?

Answer 257

• A proto-oncogene is a gene that could become an oncogene through mutation or increased activation* Most proto-oncogenes encode for proteins that regulate cell growth, adhesion or differentiation* Mutated or activated proto-oncogenes can contribute to increased or unregulated cell division, production of protein that alters the micro-environment in favour of cell growth or avoid apoptosis

Question 258

What are anti-oncogenes and how might they contribute to the development of cancer

Answer 258

• Anti-oncogenes are also called tumour suppressor genes* They help to suppress the activation of specific oncogenes - thus they can help to control cell growth, adhesion and protein production* Loss or inactivation of tumour suppressor genes due to mutation can allow activation of oncogenes

Question 259

Describe the cellular mechanisms that help prevent the development of cancer from cellular mutations

Answer 259

1. Most mutated cells have less survival capabilities than normal cells2. Most mutated cells have intact feedback controls preventing excessive growth3. The immune system can detect many mutated cells (or the products they produce) and target them for destruction * Abnormal proteins trigger either antibody production opsinization4. Multiple mutations or activation of multiple oncogenes is necessary for the development of most cancerous cells

Question 260

List the 5 major risk factors for the development of cancerous cells

Answer 260

• Ionizing radiation exposure* Exposure to carcinogens (chemicals that can cause mutations and cancer)* Physical irritants* Hereditary tendency * Likely various mutations in oncogenes are already present within the genome* Oncoviruses * DNA virus inserts directly into a chromosome * RNA virus carrying reverse transcriptase causes DNA to be generated from RNA which is then inserted into the genome

Question 261

List some of the characteristics that are unique to cancerous cells

Answer 261

1. Abnormal growth * Not bound by normal growth limis * may need less factors to grow * reduced response to inhibitors of growth2. Less adhesive than normal cells * This allows for movement between normal tissue barriers including tissue planes, entering lymphatics and blood vessels3. Production of angiogenic factors * Increases blood vessel growth and therefore provision of nutrients

Question 262

Describe the various levels of the CNSNote the basic functions performed at each level

Answer 262

1. Spinal cord * Acts as a conduit of sensory information from the periphery to the brain * Transmits signals from the brain to the periphery * Organises complex local functions * Urination * Reflexes - including withdrawal and muscle tone against gravity * Gastrointestinal movements * Regulation of vascular reflexes2. Lower brain / subcortical * Primary control centre of many “sub-conscious activities * Respiration * Blood pressure regulation * Control of equilibrium (with cerebellum) * Feeding reflexes - including initiation of salivation * Many emotional patterns including anger, excitement, sexual arousal, reaction to pain3. Higher brain / cortical * Major storehouse of information * Controls precision of responses from the subcortical regions * Thought processing

Question 263

Briefly describe the process by which a presynaptic neuron can pass a message to the post-synaptic membrane through an electrical channel.Not the important anatomical structures and provide examples

Answer 263

• Transmission through the neuronal synapse can occur via electical channels or via chemical messengers (neurotransmitters)* Electrical transmission requires a narrow synapse with direct ion channels called gap junction channels * Gap junction channels allow passage of ions directly from one cell interior to the next * The AP can be directly transmitted to the next cell * Bi-directional transmission can occur * Multiple cells with sub-threshold potentials can be detected in a cluster of inter-connected neurons* This mechanism of transmission is important in the smooth muscle and within cardiac muscle cells

Question 264

Describe the process by which a pre-synaptic neuron passes a message to a post-synaptic membrane via a chemical pathway.Note the important anatomical structures and provide examples.

Answer 264

• Using a chemical pathway, the transmission of a nerve action potential to a post-synaptic membrane requires release of a neurotransmitter from the pre-synaptic terminal * The action potential reaching the pre-synaptic terminal causes opening of calcium channels and calcium inflow * Calcium binds with protein molecules on the internal side of the membrane called release sites * This process enables vesicles containing large amounts of neutrotransmitter to bind with the membrane * The neurotransmitter is released via exocytosis* The neurotransmitter must diffuse across the synapse and bind with a receptor on the post-synaptic membrane* Neurotransmitter binding can then induce either opening of an ion channel (often sodium) or activation of a second messenger system (often coupled to a G protein)Chemical neurotransmitters allow for uni-directional message transmission.The release of acetylcholine throughout the parasympathic nervous system or noradrenaline from the SNS are examples of a chemical messenger synapse

Question 265

Describe the major differences between the ion channels and second messenger systems for post-synaptic nerve effects

Answer 265

Ion channels* Activation of an ion channel in a post-synaptic membrane is rapid* Direct opening of an anionic channel or cationic channel will directly allow transport of Na⁺ or Cl^- transfer into the cell * This ionic movement causes excitation (transmission of the AP) or inhibiton of the post-synaptic membrane respectively* The ionic channels open very briefly and after they close, the post-synaptic cell returns to baseline/normal. ie. there is no lasting change_Second messenger system_* By alteration of the cell interior via a second messenger system, lasting change or prolonged action on the post-synaptic membrane can be effected* A G-protein coupled system can cause opening of an ion channel with prolonged effect* Can cause activation of cAMP or cGMP which can alter cellular metabolism* G proteins can alter cellular enzyme expression* Gene transcription can be effected via second messenger systems

Question 266

Briefly describe the process of activation of a G-protein second messenger systemNote also how the “message” is terminated

Answer 266

• Initiation of a G-protein messenger system initially requires binding of a neurotransmitter to a receptor protein in the post-synaptic cell membrane* Binding of the receptor protein exposes a G-protein binding site due to a conformational change * Cytosolic G protein is then able to bind to the receptor* The alpha subunit releases bound GDP while binding to GTP* Simultaneously, the beta and gamma subunits are released from the protein structure* This process allows the alpha subunit, now bound to GTP, to be released from the receptor and trigger cellular actions such as gene transcription or activation of cellular enzymes* The action of the G protein is terminated when the GTP is hydrolysed to GDP on the alpha subunit * This triggers release from the target protein and re-binding with the beta and gamma subunits * The protein is inactive when all three subunits are bound together

Question 267

List the possible post-synaptic changes that can lead to an excitatory signal in the post-synaptic neuron

Answer 267

• Opening of sodium channels * Increases the membrane potential towards zero * Can rapidly elicit generation of an AP in the post-synaptic cell membrane* Reduced conduction through membrane chloride or potassium channels * Reduced influx of chloride or efflux of potassium helps increase the cell membrane potential* Alteration of cellular metabolism such that the excitatory membrane receptors increase or inhibitory receptors are decreased

Question 268

List the possible post-synaptic changes that can lead to an inhibitory signal in the post-synaptic neuron

Answer 268

• Opening of chloride channels * Allows chloride influx and increases the negative charge within the cell * Reduced cell membrane potential is stabilising/inhibitory for AP generation* Increase potassium channel conductance * Increased potassium efflux leads to reduced positivity within the cell - similar outcome as above* Activation or inactivation of cellular enzymes * Increased expression of inhibitory receptors * Decreased expression of excitatory receptors

Question 269

List and describe the important characteristics of the most common small molecule neurotransmitters

Answer 269

1. Acetylcholine * Rapidly synthesised by choline acetyltransferase from acetyl CoA and choline * Released by preganglionic nerves of the autonomic nervous system * Released by post-ganglionic nerves of the parasympathetic and some sympathetic nerves * Predominantly an excitatory neurotransmitter2. Norepinephrine * Widespread release from neurons within the brain stem * Responsible for controlling ocerall activity of the brain and wakefulness * Released by the majority of post-gangionic nerves of the SNS * Predominatly excitatory but has inhibitory effects depending on the target organ3. Dopamine * Primarily an inhibitory neurotransmitter released by neurons that originate in the substantia nigra * Mostly released into regions of the basal ganglia4. Glycine * Inhibitory neurotransmitter released at synapses in the spinal cord5. GABA (gamma aminobutyric acid) * Secreted by many areas of the spinal cord, cerebellum, basal ganglia and cortex * Primarily inhibitory in the developed brain6. Glutamate * Excitatory neurotransmitter secreted by sensory nerve terminals entering the CNS * Also released in many areas of the cortex7. Serotonin * Secreted by neurons that originate in the median raphe of the brain stem - project to many areas of the spinal cord and brain * Primarily inhibitory to the dorsal horns and hypothalamus * Inhibits transmission of pain sensation * Helps control mood and enhance sleepiness8. Nitric oxide * Produced and released by diffusion from the presynaptic nerve terminal * Minimal interaction with the post synaptic nerve cell membrane but readily diffuses into the cell * Primary action on intracellular metabolic function - specific functions are less well known

Question 270

Briefly describe the production and release of neuropeptides.Note the differences from the small molecule transmitters

Answer 270

• The neuropeptides are produced within the the cell body by ribosomes * The small molecules are produced within the cytosol of the pre-synaptic nerve terminal* They are generally formed as an integral part of a larger protein* Within the golgi, the integral protein is enzymatically cleaved into smaller fragments - the neuropeptide or a precursor * These are then packaged into minute transmitter vesicles* These vesicles are then slowly moved to the terminal nerve fibre via axonal streaming * ​This process may take weeks as the vesicles move at a few cm per day* Release is in response to AP transmission* The vesicle is then autolysed and not recycled as for the small molecule vesicles

Question 271

What is the effect of acidosis and alkalosis on the excitability of the neuron.Provide examples / outcomes

Answer 271

Acidosis* A decrease in pH greatly depresses neuronal cell excitability * A decrease towards a pH of 7.0 can result in such depression of neuronal cell activity that coma develops * This can be seen with diabetic ketoacidosis or uraemic acidosis_Alkalosis_* An increase in pH will increase the excitability of neurons * Hyperventilation triggered respiratory alkalosis can lead to epileptic seizures in a predisposed individual

Question 272

Describe the pathophysiological mechanism for reduced muscle activity in myasthenia gravis

Answer 272

• Acquired myasthenia gravis is an immune mediated disorder characterised by development of auto-antibodies against the nicotinic ACh receptor * This receptor is primarily expressed on the post synaptic membrane of the muscle* The antibodies lead to complement mediated lysis of the receptors and reduced numbers of receptors* Due to reduced receptor number, the muscles are less able to respond to release of ACh into the synaptic cleft* The congenital disease can result from a significant deficiency in the number of ACh receptors, lack of ACh or deficiencies in AChE

Question 273

Describe the pathophysiological mechanism for reduced muscle activity in botulism

Answer 273

• Botulism is caused by the toxin released from clostridium bolulinum bacteria. It is often ingestion of the toxin itself that leads to the clinical disease as opposed to tissue infection with the bacteria* The botulinum toxin effect an irreversible enzymatic cleavage of SNARE proteins within the pre-synaptic nerve terminal of cholinergic nerves * These nerves supply both the skeletal muscle and the paraympathetic nerves of the autonomic nervous system* SNARE proteins are essential for enabling the docking of ACh vesicle to the pre-synaptic cell membrane* The effects on the skeletal muscle system cause a rapidly ascending lower motor neuron (NMJ) paralysis* The autonomic effects can contribute to ileus, mydriasis, urine retention, cranial nerve deficits and megaoesophagus* Recovery occurs over 1-4 weeks and is dependent on the production of new SNARE protein (likely in the ribosomes / golgi with subsequent axonal streaming to re-populate the nerve terminal)

Question 274

Describe the pathophysiological mechanism for reduced muscle activity following elapid snake envenomation

Answer 274

• Varibale mechanisms have been proposed * Tight binding to the post-synaptic AChR , blocking neuromusclar propogation of the AP * Pre-synaptic inhibition of ACh release from the pre-synaptic nerve terminal* Reduced muscle activity may also occur due to specific toxins that contribute to primary muscle cell damage, reducing the ability of the muscles to activate and work* Reduced cholinergic activity in the parasympathetic nervous system may also contribute to mydriasis, ptyalism, ileus, dysphagia and facial paralysis (cranial nerve signs are common)

Question 275

Describe the pathophysiological mechanism for reduced muscle activity in ixodid tick paralysis

Answer 275

• Mechanism not certain* The toxin is present in the female tick saliva and released when the tick attaches and feeds* The toxin likely interferes with ACh release from the pre-synaptic nerve terminal * The mechanism for interference likely involves changes to calcium movement* Autonomic dysfunction is common with the ixodes tick, but does not occur with the American tick (Dermacentor) * The autonomic signs can include urinary retention, diastolic dysfunction and subsequent pulmonary oedema

Question 276

Describe the pathophysiological mechanism for reduced muscle activity in immune mediated myositis

Answer 276

*

Question 277

Describe the pathophysiological mechanism for reduced muscle activity in polyradiculoneuritis

Answer 277

• Evidence strongly supports polyradiculoneuritis to be caused by a type IV immune response, resulting from a shared antigen between the inciting stimulus and the peripheral nervous system * Campylobacter is the most likely causative organism, though others are possible* Campylobacter infection triggers the production of antibodies which mistakenly bind to the motor neurons in the ventral horn of the spinal cord or the peripheral nerve roots* Antibody binding enables T cell mediated damage to the nerve axon or myelin sheath * Reduced nerve AP transmission reduces release of ACh and markedly diminished muscle motor activity* Sensory nerves remain intact

Question 278

Explain the effect of carbamate and organophosphate toxicity on the neuromuscular junction

Answer 278

• Carbamates cause reversible inhibition of ACh esterase within the synaptic cleft* Organophosphates cause irrevesible enzymatic phosphorylation of AChE* AChE is important in both parasympathetic and sympathetic ganglia, parasympathic muscarinic terminals and nicotinic receptors and the NMJ* Diminished action of AChE leads to prolonged activity of ACh and repetitive AP generation in the target nerve/muscle* There is also increased neurotransmitter signalling within the brain* DUMBBELS - increased parasympathetic signalling * defecation, urination, miosis, bronchospasm, bronchorrhoea, emesis, lacrimation and salivation*

Question 279

Explain the pathophysiological mechanism for the effect of the tetanus toxin

Answer 279

• Tetanus is caused by the tetanus toxin produced by the vegetative form of the clostrium tetanii bacterium* The toxin is absorbed into the pre-synaptic membrane of the peripheral nerve* The toxin is then moved retro-axonally towards the spinal cord * Once in the spinal cord the toxin undergoes transytosis to enter the inhibitory neurons* Once in the inhibitory neuron the toxin is cleaved (pH and temperature sensitive) to release the light chain * The toxin light chain is then free to cleave synaptobrevin an important component of the SNARE protein* SNARE protein inhibition within the inhibitory neurons prevents the exocytosis of GABA and glycine, important inhibtory neurotransmitters within the spinal cord * This results in increase firing of the alpha-motor neurons - rigidity, muscle contraction and unopposed muscle spasm* Loss of inhibition of the SNS in the grey matter of the spinal cord can also lead to hypertension, high catecholamines and tachycardia

Question 280

Describe the phenomenon of fatigue at the synapse.Why and in which circumstances is this important

Answer 280

• The initial stimulation of an excitatory nerve by a neurotransmitter causes AP transmission and stimulation* With repetitive stimulation, the initial firing of the excitatory nerve is very rapid* Over milliseconds to seconds, the firing rate to the same stimulatory stimulus reduces * This reduction in firing rate is called fatigue of synaptic transmission** This fatigue is especially important in the hyper-excitable state, causing neurons to lose their excitability Fatigue likely occurs for a number of reasons: 1. Reduced stores of neurotransmitter in the pre-synaptic vesicles 2. Progressive utilisation and inactivation of the post-synaptic membrane receptors 3. Slow development of abnormal ion concentrations within the post-synaptic cell reducing the propensity for AP generation or transmissionThis may be a part of the reason for cessation of an epileptic seizure

Question 281

List the major MOTOR neuronal components within the spinal cordNote the basic structure and action of each

Answer 281

1. Anterior (ventral) motor neurons * Leave the cord via the ventral nerve roots and innervate the skeletal muscle fibres * 50-100% larger than the other neurons * Comprise both the alpha and gamma neurons2. Alpha motor neurons * Large neurons that branch to supply the skeletal muscle fibres or motor unit3. Gamma motor neurons * Smaller motor neurons that supply the smaller intrafusial fibres that are responsible for maintenance of basic muscle tone4. Interneurons * Tiny neurons present within all areas of the spinal cord * 30 times as numerous as the anterior motor neurons * Highly excitable, often with spontaneous activity * Large numbers of interconnections provide the circuitry for the intergrative functions of the spinal cord

Question 282

How is glucose released into the blood stream after ingestion of a carbohydrate

Answer 282

• Ingested carbohydrates are of the forms: * starches - large polysaccharides * Sucrose (Fructose plus glucose) * Maltose (Two glucose molecules)* Carbohydrates are digested within the gastrointestinal tract to the simple sugars glucose (80%), galactose (from lactose) and fructose * The reactions to digest the carbohydrates are catalysed by brush border enzymes together with amylase* These sugars are absorbed into the portal blood stream and are transported to the liver* In the liver, large amounts of glucose-6-phosphate together with other enzumes ensures that the majority of all monosacchraides are eventually converted to glucose* Glucose is released by the hepatocytes as required or stored in the form of glycogen via the action of glycogen synthase * Glycogen phosphatase is the enzyme responsible for slow breakdown of glycogen to glucose for maintenance of blood glucose in between meals

Question 283

Describe the process that allows glucose to readily pass from the blood into the cellular cytoplasm

Answer 283

• Glucose is transported into most tissue cells by a process of facilitate diffusion* Facilitated diffusion for glucose requires binding to a carrier protein * There are 14 GLUT proteins in humans* Facilitated diffusion happens in both direction from high concentration to low concentration* Binding of a single glucose molecule to the transporter protein enables a conformational change and passage of glucose into the cell

Question 284

Briefly describe the role and mechanism of action of insulin in cellular glucose transport

Answer 284

• Insulin greatly enhances the rate of transport by the GLUT membrane proteins* Insulin binds to an insulin receptor on cells that are sensitive to the hormone including muscle and adipose cells* Insulin binding activates a cascade of intermediate cellular products including numerous protein kinases such as protein kinase C* The casecade leads to translocation of GLUT4 proteins to the cell membrane * Increased GLUT 4 proteins enhances the rate of glucose diffusion into the cell

Question 285

Briefly describe the process of glycogen formationWhere is glycogen formed and stored

Answer 285

• Glycogen is a large polymer of glucose molecules * Most cells in the body can store small amounts of glycogen * Liver cells can store large quantities of glycogen (5-8% of their total weight * Muscle cells can store 1-3% of their total weight as glycogen* Glucose enters the cell via facilitated transport* Cellular glucokinase or hexokinase converts glucose (and other monosaccharides to glucose-6-phosphate* Glucose-6-phosphate is converted to glucose-1-phosphate * This is converted to uridine diphosphate glucose* UDG is subsequently converted to glycogen for energy storage within the cell

Question 286

Briefly describe the process of glycogenolysis (glycolysis)

Answer 286

• Glycolysis is the proces by which glycogen is broken down to form pyruvic acid, ATP and H⁺ * Pyruvic acid enters the citrate cycle to further generate energy in the form of ATP * H⁺ is converted to lactic acid for removal from the cell* Glycolysis is a 10-step process catalysed by separate enzymes* The process is initiated with splitting of glucose away from the polymer by the phosphorylase enzyme

Question 287

Which hormones can affect the rate of glycogenolysis and glycolysis

Answer 287

1. Epinephrine * activates adenylate cyclase and the formation of cAMP * cAMP activates PKA which in turn activates phosphorylase * Phosphorylase catalyses the initial step in glycogenolysis2. Glucagon * Stimulates the formation of cAMP, primarily within liver cells * Similarly to epinephine, stimulates phosphorylase and the initial breakdown of glycogen to increase glucose release and utilisation3. Insulin * Augments the cellular uptake of glucose via enhances translocation of GLUT to the cell membrane * Enhanced cell uptake of glucose promotes glycogen formation and storage of cellular energy * Insulin inactivates liver phosphorylase the initial rate limiting step of glycogenolysis * Insulin enhances both glycolysis and glycogen formation

Question 288

Briefly describe the process and importance of oxidative phosphorylation in energy generation

Answer 288

• Only small amounts of ATP are generated by the breakdown of glygoen to pyruvate - 2 ATP molecules* Similar to above, only 2 molecules of ATP are generated through the citric acid cycle* However, during these processes, hydrogen atoms are released for oxidation* Hydrogen atoms are split to form hydrogen ions and electrons* The free electrons eventually combine with dissolved O₂ and 2 x H₂O to form 3 x OH^-* OH^- Then combine to form H₂OThis process generates large quantities of ATP and occurs solely within the mitochondria

Question 289

Briefly describe the initial absorptive process for fats from the gastrointestinal tract

Answer 289

• Fats enter the gastrointesintal tract and are initially digested within bile micelles to become monoglycerides and free fatty acids* The have highly charge exterior surfaces and are soluble in the chyme* The micelles move to the brush border of the intestinal surface and are immediately dissolved into the cell through the cell membrane * The lipids are soluble within the cell membrane * This allows the bile micelles to continue digesting still more fat* They are transported within the cell to the SER where they mainly form new triglycerides (3 x monoglycerides bound by one molecule of glycerol * These form into chylomicrons - triglycerides in the centre with some cholesterol surrounded by a phospholipid and apolipoprotein shell* The chylomicrons once formed are secreted from the basolateral surface of the epithelial cell and taken up by the lymph

Question 290

Describe the process of chylomicron digestion to enable storage of fat within the body’s cells

Answer 290

• Lipoprotein lipase is expressed in many cells, especially adipose, skeletal muscle and cardiac cells* This enzyme is transported to the surface of capillary endothelial cells * Hydrolyses the phospholipids and triglycerides within the chylomicrons as they contact the endothelial wall* Hydrolysis of triglycerides releases free fatty acids and glycerol* Fatty acids can dissolve in the cell membrane and diffuse across into the cytoplasm * These can then be used for energy generation or fat storage* The fat storage cells synthesize glycerol which enables the conversion of free fatty acids back into triglycerides

Question 291

What is the purpose of triglyceride hydrolysis?Describe the triggers for triglyceride hydrolysis

Answer 291

• Triglycerides are utilised throughout the body for the storage of energy* When this energy is required in other parts of the body, such as during fasting, triglycerides must be released into the blood for transport* Triglycerides are predominantly hydrolosed to free fatty acids and glycerol for transport to other parts of the body* Reduced glucose availability to the storage cells will trigger hydrolysis * One of the glucose breakdown products is necessary for maintenance of the glycerol portion of triglycerides. * When this product (alpha-glycerophosphate) is low, the glycerol is hydrolysed* Hormone sensitive lipase can also promote rapid hydrolysis

Question 292

Briefly describe the functions of the adipose tissue

Answer 292

1. Energy storage in the form of triglycerides2. Heat / cold insulation3. Hormone secretion * Leptin * Adiponectin * Both have an effect on appetite and energy expenditure

Question 293

Briefly describe the role of the liver in lipid metabolism

Answer 293

1. Degrade fatty acids into the small molecules that can be used for energy * acetyl-CoA2. Synthesize triglycerides * Predominantly from carbohydrates * The liver is the primary source of unsaturated (or desaturated) triglycerids * Under the action of a dehydrogenase3. Synthesize other lipids, mainly from fatty acids * cholesterol * phospholipid

Question 294

What is the role of carnitine in fatty acid oxidation

Answer 294

• Carnitine is present with the cytoplasm* Carnitine acts as a carrier to transport fatty acids into the mitochondria from the cytosol* Upon entry into the mitochondria, carnitine splits from the fatty acid * The fatty acid is then free to be degraded and oxidised

Question 295

Briefly describe the steps involved in beta oxidation.

Answer 295

1. Fatty acid is transported into the mitochondria in combination with carnitine * Carnitine is split away2. The fatty acid combines with Coenzyme A and ATP to form fatty acyl-CoA3. The second carbon from the CoA binds with oxygen * The beta carbon becomes oxidized4. The 2 carbon portion of the fatty acid is released as acetyl CoA5. Another CoA molecule binds to the new beta carbon and the process repeats6. Acetyl CoA can enter the citric acid cycle for ATP and H⁺ generation

Question 296

The liver can produce acetyl CoA at a rate excessive to its metabolic demand. How is this additional acetyl CoA eventually utilised by other cells.What are the intermediary products that are formed

Answer 296

• When the acetyl CoA is excessive to cellular needs, two molecules condense to form one molecule of acetoacetic acid* Acetoacetic acid is released into the blood stream and can be transported throughout the body* A part of the acetoacetic acid is converted to beta-hydroxybutyric acid and minute quantites are converted to acetone * Acetoacetate, beta-hydroxybutyric acid and acetone diffuse freely through the cell membrane* These ketone bodies are produced readily and in large quantities* However, as they are rapidly transported and very readily absorbed by the cells, the blood levels remain low

Question 297

Under what conditions does ketosis occur and in which circumstances will ketones become increased in the body

Answer 297

• Ketosis is the process by which ketones are produced during fatty acid metabolism* Ketosis occurs when there are not enough carbohydrates or glucose within the body to provide adeuqate fuel for energy generation* Ketones are produced after beta-oxidation of fatty acids * 2 molecules of acetyl-CoA combine to form acetoacetic acid * Acetoacetic acid is then partly converted to beta-hydroxybutyric acid and acetone* Ketones can increase in the body whenever there is insufficient carbohydrate to provide energy * Starvation * Dietary manipulation - high fat / high protein, ultra-low carbohydrate * Diabetes mellitus - insulin deficiency leads to cellular depletion of glucose due to reduced GLUT facilitated transport

Question 298

Briefly describe the important steps in conversion of glucose to triglycerides (lipogenesis)

Answer 298

• Carbohydrates are converted into acetyl-CoA* Acetyl CoA is converted to Malonyl CoA via a carboxylation reaction* The malonyl-CoA undergoes esterification with additional carbon pairs added* Once the fatty acids are ~14-18 carbons in length, they are transported to the SER where 3 FA are combined with one glycerol molecule by a dehydration reaction* Glycerol is provided to the SER via glucose metabolism - production of alpha-glycerophosphate * Therefore, reduced glucose metabolism inhibits formation of triglycerides

Question 299

Note the major metabolic pathways that are interruptued in the absence of insulin

Answer 299

1. Reduced glucose transport into the cell * Reduced glucose metabolism into pyruvic acid * Reduced acetyl CoA to the citric acid cycle * Reduced alpha glycerophosphate - reduced glycerol for triglyceride formation2. Increased proteolysis and catabolism3. Increased beta-oxidation of triglycerides / fatty acids * Increased lipolysis4. Reduced glycogen synthesis * Reduced activation of phosphofructokinase and glycogen synthase5. Increased gluconeogenesis6. Increases arterial smooth muscle tone

Question 300

Briefly explain the equilibrium between free fatty acids, triglycerides and the effect of changing glucose levels

Answer 300

Fats are present in adipose cells as two forms - triglycerides or free fatty acids* When there is excess glucose available - increased alpha-glycerophosphate present (from glucose metabolism), more triglycerides are formed (fatty acids reduced) * This process effectively binds the fatty acids so they are less available to be used for energy generation* Secondly, when glucose is available, acetyl CoA is rapidly produced * High quantities of acetyl CoA in conjunction with reduced free fatty acids promotes the formation of more fatty acids to balance the equilibrium* Furthermore, the intermediaries of the citric acid cycle accelerate the acitivity of acetyl-CoA-carboxylase. * This enzyme catalyses the rate limiting step of carboxylation of acetyl-CoA into malonyl-CoA, the first step in fatty acid synthesis

Question 301

What is an adipokine?List some of the known and important adipokines

Answer 301

• An adipokine is a cytokine secreted by adipose cells* Over 100 biologically active adipokines have been discovered1. Leptin2. Adiponectin3. Angiotensinogen4. Apelin5. Chemerin6. IL-67. TNF-a8. Plasminogen activator inhibitor9. Visfatin10. CRP

Question 302

What are the 2 major known actions of the adipokines

Answer 302

• Regulators of inflammation * Can be pro- or anti-inflammatory* Affectors of energy balance by promoting insulin resistanceThe adipokines can have local (apocrine) or systemic (endocrine) effects

Question 303

What are the roles of the adipokine hormone leptin?

Answer 303

1. Anti-obesity hormone * Leptin increases with increasing body condition * Binds to brain receptors (OB-R) and suppresses food intake, increases energy expenditure and influences food related behaviour2. Stimulates angiogenesis3. Inhibits apoptosis4. Acts as a mitogen5. Regulates immune and reproductive function6. Modulates insulin sensitivity7. Exerts an pro-inflammatory and pro-thrombotic effect8. Inhibits aponectin

Question 304

Briefly describe the leptin levels in dogs and cats that are a good body condition or obeseHow might those levels change after a meal?

Answer 304

• Most obese animals have higher serum leptin than those of thin animals* Resistance to or lower sensitivity to leptin may be reduced or defective receptors or reduced tissue signalling* In obese dogs, a study observed increased leptin levels and deficient leptin transport across the blood-brain barrier* In dogs, leptin levels can double or triple after eating when compared to fasted dogs* In cats, there is a mild increase after a meal only

Question 305

Briefly describe the proposed effects and regulation of adiponectin

Answer 305

• Adiponectin is most likely secreted by mature adipocytes* Serum adiponectin is reduced in obese animals * Possibly due to inhibition by inflammatory cytokines* Effects are target organ mediated * Increased insulin sensitivity * Lower serum glucose levels * Reduced liver and muscle triglyceride concentrations * Stimulates beta-oxidation and use of glucose together with reducing hepatic gluconeogenesis * Reduced inflammatory responses (anti-inflammatory) * Reduced atherosclerosis in humans

Question 306

Adipose is an important source of angiotensinogenBriefly explain how increased angiotensinogen contributes to morbidity in obesity

Answer 306

1. Angiotensinogen is the precursor molecule to angiotensin2. Angiotensins modulate and upregulate adipose tissue lipogenesis3. Angiotensin can down-regulate lipolysis4. They also play a role in adipose cell differentiation5. Enhanced activation of the local tissue RAAS may play a role in local tissue inflammation6. May allow insulin resistance to progress7. May increase the production of leptin8. May supress the production of adiponectin

Question 307

Describe the function, regulation and production of ghrelin

Answer 307

• Ghrelin is known as the hunger hormone* Synthesized in the oxyntic glands within the gastric fundus* It is the only known orexigenic (appetite stimulating) hormone* It is produced after fasting, crosses the blood-brain barrier and binds to receptors to: * Stimulate appetite * Stimulate production of growth hormone* Maximal levels are produced after overnight fasting and reduce ~1 hour after eating* Ghrelin levels are decreases in obese animals and increased in anorexic animals* Ghrelin decreases less after high fat ingestion versus high carbohydrate ingestion* The decreas in ghrelin levels is also less in obese versus lean (people)

Question 308

Describe the function, regulation and production of cholecystokinin

Answer 308

• CCK is an anorexigenic hormone produced by the L-cells of the SI * Production is stimualted in response to food intake* CCK stimulates pancreatic and biliary secretions, thereby promoting digestion* Exerts a negative feedback effect on appetite centrally* Effects a delay in gastric emptying* CCK increases more rapidly and to a higher level in lean versus obese (people)* Post-prandial levels are higher afer a high-fat meal* CCK is important in regul;ating food intake - there is no celar link with obesity

Question 309

Describe the function, regulation and production of glucagon like peptide-1 (GLP-1)

Answer 309

• GLP-1 is produced by the intestinal L-cells, plus lesser levels from the pancreas and hypothalamus* Secretion is stimulated by: * Food in the small intestine * Glucose and fatty acid concentrations * Vagus nerve stimulation* Stimulates beta-cell synthesis of insulin* Inhibits alpha-cell secretion of glucagon* Similar to CCK * Suppresses appetite in the CNS and decreases gastric emptying * Levels are higher after a high fat meal* Post-prandial production is reduced in obese people, but increased in dogs with obesity

Question 310

What is the major pathophysiological cause of inflammation in obesity

Answer 310

• Increasing, especially rapidly increasing numbers of adipocytes causes a relative reduction in vascularisation and reduced local oxygen tension* This leads to increased secretion of angiogenic and cytokines, some of which are pro-inflammatory mediators* Monocyte chemo-attractant protein-1 (MCP-1) production is enhanced leading to increased numbers of macrophages in the expanding adipose tissue* Macrophages can produce pro-inflammatory mediators such as TNF-a and IL-6. * An imbalance between pro-inflammatory and anti-inflammatory macrophage subtypes may be present with obesity

Question 311

Describe the role of the major obesity induced pro-inflammatory mediators

Answer 311

• Increased pro-inflammatory macrophages associated with obesity produce increased levels of TNF-a, IL-6 and CRP_TNF-a:* Produced by numerous other cells in conjunction with macrophages* Anti-tumour activity* Blocks insulin receptor activation leading to insulin resistance* Also involved in systemic inflammatory responses, auto-immune disorders, septic shock and fever_Interleukins: (especially IL-6)* Increased IL-6 during obesity is released into the portal circulation and stimulates hepatic triglyceride secretion* This leads to a reduction in hepatic insulin sensitivity_CRP:_* CRP is generated in the liver in response to increased IL-6 and TNF-a* CRP can heighten the inflammatory response

Question 312

List the various metabolic or mechanical conditions that have been associated with obesity

Answer 312

1. Osteoarthritis2. Insulin resistance and type II diabetes3. Dyslipidaemia4. Cardiovascular conditions5. Kidney disease6. Neoplasia7. Respiratory disease8. Neurological consequences

Question 313

Describe the endocrine pathways of insulin resistance (or development of type II diabetes) in association with obesity

Answer 313

The following changes occur with obesity:* Increased fatty acid concentrations * This activates protein kinases that can adversely effect insulin receptor function* Increased adipose derived hormones including leptin, adiponectin, resistin etc. * Leptin can decrease insulin sensitivity, while adiponectin acts to increase sensitivity * Adiponectin production decreases in the obese * Resistin is increased in obesity and promotes the expression of the suppressor of cytokine signalling-3 (SOCS-3), a negative regulator of insulin sensitivity

Question 314

Describe the inflammatory pathways of insulin resistance (or development of type II diabetes) in association with obesity

Answer 314

• TNF-a and IL-6 levels are increased with obesity* The Jun-terminal protein kinase 1 (JNK-1) is activated by TNF-a * This leads to a phosphorylation reaction that effectively weakens the action of insulin at the insulin receptor * JNK-1 leads to hyperglycaemia and hyperlipidemia by reducing Insulin repector substrate (IRS) and SOCS-3* Retinol binding protein (RBP), produced int he liver and adipose cells increases with obesity * RBP inactivates GLUT-4 in adipose tissue

Question 315

List the various plasma lipoproteinsNote the major structural differences between the different lipoproteins

Answer 315

1. Chylomicrons2. Very low density lipoprotein3. Intermediate density lipoprotein4. Low density lipoprotein5. High density lipoprotein

Question 316

Note the major functional differences between the different lipoproteins

Answer 316

1. Chylomicron * ​Carry triglycerides from the gut to the liver2. VLDL * Carry newly synthesized triglycerides from the liver to tissues3. IDL * Intermediate between VLDL and LDL4. LDL * Carry 3-6,000 fat molecules as phospholipids, cholesterol and triglycerides (and others)5. HDL * Primarily collect fat from the body and transport it back to the liver * Produced within the liver as a complex of phospholipids and apolipoproteins * Initially cholesterol free, they scavenge cholesterol from the body

Question 317

Describe the major pathophysiological links between obesity and heart disease

Answer 317

• Obesity leads to an increase in effective circulatory volume and peripheral vascular resistance * This combination increases the incidence of hypertension* There is subsequent eccentric hypertrophy or concentric hypertrophy depending on the combination of changes to ECV and PVR* Abdominal obesity has been associated with diastolic dysfunction and reduced systolic dysfunction in dogs * Diastolic dysfunction can lead to portal congestion, portal vein thrombosis and myocardial hypoxia* Note the apparent paradox that weight gain after the onset of heart failure has been associated with an improved survival * This may be more due to the lack of weight loss and cachexia as opposed to the actual weight gain

Question 318

Describe the pathophysiological association between obesity and renal disease

Answer 318

• Obesity leads to an increase in ECV, SNS activation, RAAS activation (production of angiotensinogen)* Lipid metabolism may lead tp an increase in renal toxic metabolites* Increased due to Na⁺ resorption - increased ECV and BP * Initially countered by an increased GFR and BPWith chronicity, the following can contribute to progressive renal damage:* Renal vasodilation* Renal hyperfiltration* SNS and RAAS activation* Metabolic disease* Chronic inflammatory stateLeptin, which activates the SNS to exert its central function may also be important in raising BP in obese animals

Question 319

What are cachexia and sarcopenia?List some of the more common disease processes known to contribute to cachexia

Answer 319

• Cachexia is the loss of lean body mass in association with disease* Sarcopenia is the loss of lean body mass in the absence of a specific underlying disease1. Neoplasia2. Cardiac disease3. Kidney disease4. COPD

Question 320

Describe the four major aspects of cachexia pathophysiology

Answer 320

1. Increased energy utilisation2. Decreased nutrient absorption * Altered GIT structure or function3. Decreased nutrient intake * Medication side-effect * Dysregulation of the satiety signalling process * ghrelin, adiponectin, leptin, serotonin, insulin etc * eg. resistance to or reduced production of ghrelin or adiponectin * eg. increased sensitivity to the satiety signalling leptin4. Altered metabolism * ​Essentially an imbalance between protein synthesis and catabolism * May be influenced by inflammatory mediators * Especially increases in TNF-a * Increasing metabolic demand such as in sepsis or with SNS activation as seen with CHF

Question 321

Briefly describe the major inflammatory mediators of cachexia

Answer 321

• Increased inflammatory cytokine production is a major cause of cachexia* TNF-a, IL-1 and IL-6 are primary contributors to cachexia as they all: * Reduce appetite * Increase basal metabolic rate * Accelerate loss of lean body mass* The activity of these cytokines is primarily mediated by activation of Nucelar Factor kappa-B (NF-kappa-B) * Which activates the ubiquitin proteosome pathway and leads to muscle cell atrophy and decreased muscle regeneration

Question 322

What is myostatin?How are myostatin concentrations altered in chronic inflammatory disease and what is the effect?

Answer 322

• Myostatin is a member of the transforming growth factor beta superfamily * Negatively regulates muscle mass* Exercise decreases myostatin levels, whereas chronic inflammation can increase myostatin* TNF-a and angiotensin II can increase myostatin levels in CHF, augmenting the effects of cachexia

Question 323

In addition to the inflammatory cytokines, which hormones are known to contribute to cachexia in CHF

Answer 323

• Catcholamines * Activation of the SNS* RAAS activation* Cortisol* Atrial natriuretic peptide* Brain type natriuretic peptide

Question 324

Briefly describe the absorption and distribution of amino acids within the body

Answer 324

• Amino acids are absorbed directly from the gastrointestinal tract (SI) * Ingested protein is digested by proteases such as trypsin and absorption across the luminal epithelial membrane occurs via facilitated or active transport* The amino acids are in part stores within the epithelial cells and then transported to the liver via the portal veins. As protein digestion and absorption is slow, there is minimal increase in systemic blood amino acids following a protein meal* The liver cells take up amino acids and produce proteins (polymerised amino acids - via peptide linkages) in the RER. * These proteins can be rapidly digested by cellular lysosomes to free amino acids* Most cells produce their own proteins from amino acids absorbed directly from the blood

Question 325

Briefly note the importance of the liver in maintaining protein and amino acid equilibrium within the body

Answer 325

• Amino acids are supplied directly to the liver following protein digestion and absorption in the gut* Amino acids are readily transported into the liver cells* The liver cells rapidly synthesize proteins from the available amino acids * These proteins in part serve as a storage pool for the amino acids* The liver cells can rapidly degrade the cellular proteins (fusion with lysosomes) to provide amino acids to the circulation* Amino acids are maintained at a fairly constant level in the systemic circulation

Question 326

Describe the potential fate of amino acids after they enter the body

Answer 326

• The majority of amino acids are utilised by the body’s cells to produce proteins* Each cell has an upper limit for protein storage and excess amino acids can be converted and used for energy generation * Deamination is the initial step for protein amino acid conversion and occurs almost entirely within the liver * Deamination converts the amino acids to keto-acids * This process generates ammonia as a waste product which is excreted primarily in the form of urea* Following deamination, the keto acids are converted to substances such as pyruvic acid or acetyl CoA * This can then be: * used for energy generation in the citric acid cycle * Stored as triglycerides * Stored as glycogen

Question 327

Note the major hormones involved in protein regulationNote each hormones basic mechanism of action on protein metabolism

Answer 327

1. Growth hormone * Increased tissue protein quantity * Likely due to increased amino acid transport and acceleration of DNA and RNA transcription and translation in the ribosomes2. Insulin * Increases protein synthesis by increasing amino acid transmembrane transport * Ensures adequate glucose within cells for energy generation, reducing protein degradation3. Glucocorticoids * Decrease protein content in most tissues by increasing the rate of breakdown * Increase plasma amino acid concentrations * Increases liver and plasma proteins4. Testosterone * Encourages increased protein deposition especially in the contractile proteins of muscle cells * Unlike GH, there is a limit to the increased protein content that can be caused by testosterone5. Estrogen * Similar to testosterone but less effective6. Thyroxine * Increases the basal metabolic rate * Leads to increased and rapid protein degradation in the absence of adequate glucose * Leads to rapid growth and protein synthesis as long as there is adequate other energy sources * eg. thyroxine deficiency during the growth phase causes marked stunted growth

Question 328

List the different factors that contribute to heat production in the body

Answer 328

Heat production is determined by the metabolic rate1. Basal metabolic rate2. Extra metabolism caused by muscle activity3. Extra metabolism caused by the effect of thyroxine * and other hormones including GH and testorsterone4. Extra metabolism caused by sympathetic activity, NE and epi5. Extra metabolism caused by increased chemical activity6. Extra metabolism needed for digestion, absorption and food storage

Question 329

Describe the various physiological mechansims by which heat is lost from the skin

Answer 329

1. Radiation - loss via infrared heat rays2. Conduction * Energy is transferred to the air via conduction of kinetic energy in the form of vibrations * Once the surrounding air reaches body temperature, conduction from the body ceases unless convection occurs3. Convection * Air movement removes the heat loss to the air via conduction4. Heat loss to water * The ability of water to absorb heat is many thousand times greater that air. No insulation can occur and heat loss is much greater5. Evaporation * Heat loss via sweat is in addition to the insensible lossed from the skin and lungs

Question 330

Describe the mechanism of panting in animals and why it is necessary

Answer 330

• Panting is a necessary thermoregulatory system in dogs (and cats) as they have fur that minimises heat loss via conduction and convection and they have no sweat glands in the skin preventing significant evaporation* Panting si triggered by the thermoregulator centre in the hypothalamus* Panting is controlled by the panting centre in the pneumotaxic respiratory centre in the pons* Air rapidly passes over the respiratory secretions, especially the saliva on the tongue and oral mucosal surfaces* Alveolar minute ventilation is not significantly altered as the breaths are very shallow and mainly involves movement of the dead space air

Question 331

Describe the role of the hypothalamus in maintenance of a normal body temperature

Answer 331

• Heat sensitive neurons present in the anterior-preoptic hypothalamus (and ~1/3 as many cold-sensitive neurons)* These neurons increase their firing rate with an increase or decrease of body temperature respectively* Temperature receptors in the skin are much more adept at sensing cold versus warmth * Similarly, the temperature sensors in the deeper tissues detect mainly cold rather than warmth* The peripheral and anterior hypothalamic signals are transmitted to the posterior hypothalamus* Heat and cold signals from the body and centrally are combined and integrated in the posterior hypothalamus to effect heat preserving or heat producing reactions of the body

Question 332

Describe the major mechanisms for reducing the body temperature

Answer 332

• Vasodilation of the skin blood vessels * Increase blood flow to the skin increases the rate of heat conduction away from the body * Caused by inhibition of the sympathetic centres in the posterior hypothalamus* Sweating * Less important in animals* Panting * Increased convection of air across moist mucosal surfaces of the oral cavity and tongue* Decrease heat production * Minimise chemical thermogenesis and activities such as shivering

Question 333

Describe the mechanisms by which the body can increase temperature in response to cold

Answer 333

• Vasoconstriction of the skin blood vessels * Mediated by sympathetic stimulation of the posterior hypothalamus* Piloerection * Sympathetic stimulation of the arrector pili muscles * These muscles attach to the hair follicles and cause the hairs to stand upright * This increases air trapping around the body and reduces conductive and convective heat loss* Increased thermogenesis * Shivering causes heat production in the muscles * Heat production by sympathetic stimulation * Thyroxine stimulation - increases metabolic activity

Question 334

Describe the physiological process of shivering

Answer 334

• Shivering is triggered by the posterior hypothalamus* The shivering centre is triggered when heat signals from the anterior hypothalamus reduce and cold signals from the periphery increase* A signal is sent from the shivering centre through bilateral tracts of the brain stem and lateral spinal cord and eventually to the anterior motor neurons and skeletal muscles* The signals and non-rhythmic and cause an increase in skeletal muscle tone* When the tone rises above a criticl level, shivering begins due to feedback oscillation of the muscle spindle strethc reflex mechanism* Shivering can increase heat procution by four to five times normal

Question 335

Define feverWhat are the major causes of fever?

Answer 335

• Fever refers to a body temperature that is above the usual range of normal* Exercise* Environmental / heat stroke* Exogenous pyrogens - bacterial infection* Brain lesions

Question 336

What is a pyrogen?Explain the mechanism of action of pyrogens in causing a fever

Answer 336

• A pyrogen is any substance that can cause a rise in the set-point of the temperature control centre in the hypothalamus* Some pyrogens act directly on the hypothalamus, however, most act through the production of cytokines in concert with the immune system* Bacteria or bacteria breakdown products are ingested by macrophages or LGLs (killer T cells) which subsequently produce cytokines in response - as for the innate and adaptive immune systems* The cytokines, especially IL-1, circulate through the body fluids * IL-a can effect a change to the hypothalamic set-point within 8-10 minutes* IL-1 causes fever first by stimulating production of PGE₂ or other prostaglandin * The protaglandin acts on the hypothalamus to elicit the fever reaction

Question 337

Define heat stroke

Answer 337

• Heat stroke is a severe elevation in body temperature from 40.5 C to 43.0 C after an animal has been exposed to elevated ambient temperatures or performed strenuous exercise

Question 338

Briefly outline the major pathophysiological changes that can occur during heat stroke

Answer 338

• Initially, panting is triggered in the panting centre (within the respiratory centre in the pons). * This reflex starts the process of heat dissipation as long as the relative humidity is not too high* As the body temperature rises, metabolic rate also rises, compounding the heat gain if dissipation cannot occur * Behavioural mechanisms such as seeking shade or cool surfaces help minimise heat gain* With continuation, metabolic acidosis can occur* * Peripheral vasodilation occurs * To help maintain blood pressure, splanchnic constriction occurs (SNS mediated)* Increased SNS activation and circulating catecholamines lead to an increased heart rate and cardiac output* With progression and development of metabolic acidosis, cardiac output will reduce and perfusion especially to vital organs will reduce* Likely due to over-production of nitric oxide, splanchnic vasodilation eventually occurs * This leads to blood pooling, reduced venous return and a marked drop in cardiac output* This triggers the initial signs of shock with decreased perfusion, intestinal ischaemia, hypoxia and endothelial cell damange - leads to increased vascular permeability* Direct hyperthermia can also trigger inflammatory, hemostatic and tissue damage processes * SIRS which can progress to MODS * Coagulation defects such as DIC * Ischaemic necrosis - further precipitates the above

Question 339

List the potential major pathophysiological complications following a severe bout of heat stroke

Answer 339

• SIRS* DIC* ARDS* Rhabdomyolysis* Acute kidney injury* Hepatic damage* Neurological damage* Acute pancreatitisHaemodynamic deterioration and pulmonary lesions are the major causes of death

Question 340

Briefly describe the clinical neurological abnormalities seen in dogs with heat stroke.What are the underlying pathophysiological mechanisms for the neurological abnormalities?

Answer 340

• Neurological abnormalities are commonly seen with moderate to severe heat stroke * Altered consciousness or disorientation * Stupor * Seizures * Coma* In pathological studies of fatal heat stroke the following findings have been reported: * cerebral oedema * haemorrhage * hyperemia * neuronal necrosis* Direct thermal injury may play a minor role in the clinical signs* More likely, the abnormalities are caused by shock and cerebral hypoperfusion / cerebral hypoxia* MODS and metabolic derangements such as metabolic acidosis and respiratory alkalosis, hypoglycemia and haematological/coagulation abnormalities including DIC

Question 341

Describe the potential haematological derrangements that can be seen secondary to moderate and severe heat stroke

Answer 341

• Initial sympathetic drive causes widespread superficial vasodilatation and reduction to peripheral vascular resistance* Diffuse thermal injury to the vascular endothelium triggers many aspects of the coagulation cascade * Vascular endothelial injury exposes tissue factor * TF combines with F VII to activate the TF (extrinsic) pathway * Kallikrein and Factor XII are also activated leading to activation of the contact activated (intrinsic) pathway* Diffuse multi-organ themal or hypoxia induced necrosis also stimulates the coagulation cascade* Direct hepatocellular injury may further precipitate coagulation abnormalities as both clotting factors and anti-thrombotic proteins are reduced* Elevated temperatures enhances platelet activation, coagulation and fibrinolysis * This combination leads to increased utilisation of platelets and coagulation factors - the initiating process for DIC development* Note: increase in PT, aPTT, and reduced protein C together with hypofibrinogenemia at 12-24 hours post presentation was significantly associated with death.

Question 342

Describe the pathophysiological mechanisms for the development of acute kidney injury in moderate to severe heat stroke

Answer 342

• At presentation, renal function issues may be difficult to detect* The mechanism of renal injury is likely multifactorial * hypoperfusion - distributive shock and dehydration * direct thermal injury * endotoxemia * myoglobinemia * release of cytokines and vasoactive substances * vascular injury due to microthrombi, especially with DIC

Question 343

Briefly comment on the availability of biomarkers to detect early AKI in dogs

Answer 343

• Early AKI is difficult to detect as injury and reduced GFR occur prior to the onset of elevated serum creatinine* Early detection may be helpful in cases where AKI might be anticipated and contribute to mortality if not appropriately addresses early in the course of a disease * Eg. shock, heat stroke, any cause of DIC, sepsis etc. * AKI is invariably present in dogs with heat stroke_Biomarkers:_ all with creatinine ratios* urine neutrophil gelatinase associated lipocalin* urine retinal binding protein* urine protein creatinines ratio - median of 4.8 at the time of presentation* Fractional excretion of sodium is invariably reduced* GFR reduced* Serum creatinine normal to mild increases early in disease

Question 344

Describe the pathophysiological consequences to the gastrointestinal tract following moderate to severe heat stroke together with the more widespread implications

Answer 344

• The primary inciting cause for GIT injury following heat stroke is blood flow re-distribution * Cutaneous vasodilatation is combined with visceral vasoconstriction * The high metabolic activity of gastrointestinal epithelial cells makes them particularly susceptible to periods of reduced blood flow, hypoxia and ischemia* Splanchnic vasoconstriction and local hyperthermia stimulates production of nitric oxide with resultant vasodilatation * Splanchnic vasodilatation in this manner occurs immediately before vascular collaspe as it is associated with a marked reduction in venous return due to blood pooling* Epithelial damage leads to impaired mucosal barrier function and increased permeability * Bacteria and endotoxin translocation * endotoxin can worsen SIRS and can potentially lead to sepsis, MODS and death