Physiology Review Flashcards
Describe the two types of diffusion and the factors that determine the rate of diffusion
- 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
Describe how the protein channels can selectively allow passage of water and other substances
- 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
Briefly describe facilitated diffusion.
- 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
Note two of the most important examples of facilitated diffusion within the body
- 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
What is active transport?Provide an example
- 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
Briefly note the action of the sodium potassium pump
- 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
Describe the vital roles of the sodium and potassium pump with regards to cell homeostastis and function
- 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
Describe the pumps responsible for maintaining intracellular cytosolic calcium at ~ 10,000 time less than the extracellular fluid
- 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
Briefly describe co-transportGive an example of a co-transport mechanism
- 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.
Describe the process of transport across cellular sheets.Where is this process most important
- 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
What is the resting membrane potential?How does the resting membrane potential originate?
- 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
What is an action potential?
- 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
Describe the three stages of the action potential
- 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
Describe the 4 channels that are involved in the ion flows during propogation of an action potential
- 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
Briefly describe the role of calcium in the generation / propogation of the action potential
- 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
Describe the changes that lead to increased excitability of cell membranes when there is a calcium deficit
- 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
Briefly describe the ionic changes that trigger generation of an action potential
- 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
Describe how a single action potential can propogate along the entire length of the axon / cell membrane
- 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
What is myelin and how is it produced
- 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
How does myelin affect and influence nerve cell AP transmission
- 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
Discuss the benefits of conduction along myelinated nerves
- 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
What are the major triggers that lead to generation of an action potential.Provide an example of each
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
Describe the general mechanism of muscle contraction
- 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.
Describe the three sources of enegy that are utilised for muscle contraction.Note that the energy is provided in the form of ATP
- 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
Describe the characteristics of slow muscle fibres
- 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
Describe the characteristics of fast muscle fibres
- 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
Describe the important neurological aspects of the maintenance of normal skeletal muscle tone
- 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
Briefly describe the cellular process that lead to muscle fatigue
- 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)
Describe the major components of the neuromuscular junction
- 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
Describe the process by which acetylcholine is released from a pre-synaptic nerve terminal
- 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
Briefly describe the interaction between acetylcholine and the acetylcholine receptor together with the down stream effects
- 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
Describe the various drugs or processes that can alter the function of the neuromuscular junction
- 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
Describe the movement of calcium ions into and out of the sacoplasmic reticulum during muscle contraction
- 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
Briefly describe the suspected pathophysiology of malignant hyperthermia
- 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
List the classical clinical signs associated with malignant hyperthermia
- 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
Describe the treatment recommendations for malignant hyperthermia
- 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
Note the major anatomical similarities and differences between smooth and skeletal muscle
- 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
Describe the 5 ways in which the various types of smooth muscle are distinctive
- Physical dimensions2. Organisation into bundles or sheets3. Response to different types of stimuli4. Characteristics of innervation5. Function
What are the characteristics of multi-unit smooth muscle?
- 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
What are the major characteristics of unitary smooth muscleProvide examples of unitary smooth muscle
- 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
Describe the structures of smooth muscle as they relate to contractile ability
- 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)
Describe the contrasting characteristics of smooth versus skeletal muscle contraction at a cellular level
- 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
Describe the role of calcium and calmodulin in smooth muscle contraction
- 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
Describe the way calcium is modulated and altered and the effect on smooth muscle contraction
- 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
Describe the various stimuli that elicit an AP in smooth muscle
- Electrical impulse - from neurons* Chemical message * Hormones* Stretch receptors* Spontaneous generation within the fibre itself
Describe how and why smooth muscle can produce an action potential with a plateau
- 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
Describe the slow wave potential present in numerous smooth musclesWhy is the slow wave potential important?
- 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
Describe the various local control signals for smooth muscle contraction, giving examples.
- 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
List the various hormones that can have an effect of smooth muscle tone
- Epinephrine* Norepinephrine* Angiotensin* Endothelin* Vasopressin (ADH)* Histamine* Oxytocin* Serotonin
Describe the mechanisms by which the excitability of smooth muscle can be increased or decreased by the effect of hormones.
- Various hormones bind to receptors that will then directly impact the state of either sodium or calcium channelsExcitation* 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
Briefly describe the actions and interactions of the two major smooth muscle neurotransmitters
- 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
Describe the three basic principles that underlie circulatory function
- 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
Describe the relationship between vascular pressure and distensibilityHow does this relationship affect the arterial pressure in the systemic versus pulmonary circulation
- 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
Describe vascular compliance and the relationship between compliance and vascular distensibility
- 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
Describe the effect on the arterial and venous systems with both sympathetic stimulation and inhibition
- 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
Describe delayed- and reverse delayed-compliance
- 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
How does arterial distensibility affect tissue blood flow. Describe the differences in blood flow if the arteries were poorly distensible
- 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
Describe the process by which an automated oscillometric blood pressure machine can determine systolic, mean and diastolic blood pressure
- 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
Describe the relationship between central venous pressure and the function of the right heart
- 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
Describe the peripheral venous circulation factors that can lead to an increase in CVP
- 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
Describe the branching and anatomical structures from arteries to the level of the capilliary
- 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
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
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
Describe the forces that ensure appropriate movement of fluid between the capillary and the interstitial space
- 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
Describe the anatomy of the terminal lymphatic capillaries and the special function that this anatomy allows
- 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
Describe the formation of lymph and relative components in the periphery and contrast with the thoracic duct
- 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
Describe the various mechanisms that contribute to the normal flow of lymphatic fluid
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
Briefly describe the two major theories that best explain the regulation of local blood flow
- 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.
Describe the two proposed theories that explain why blood flow drops towards normal after a sudden rise in blood pressure
- 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
Describe the special mechanism of tubuloglomerular feedback as it operates within the kidney
- 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
What two triggers other than oxygen concentration can significantly alter blood flow within the brain
- 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+
Describe the special mechanisms that can alter cutaneous and subcutaneous blood flow
- 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)
Describe the metabolism and action of nitric oxide
- 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
What are the triggers for nitric oxide release
- 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
Describe the metabolism and action of endothelin
- 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
Briefly discuss the mechanism for adaptation to chronic changes in local blood flow.Comment on both new growing tissue and established or older tissue
- 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
Note the 4 best described vascular growth factorsNote the pathway for release of these factors
- 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
Briefly describe the process of angiogenesis in response to a vascular growth factor
- 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
List the 4 most important vasoconstrictors
- Norepinephrine* Epinephrine* Vasopressin (ADH)* Angiotensin II
Briefly describe the dual action effect of NE and Epinephrine on vascular tone
- 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
Briefly describe the metabolism and role of bradykinin in vascular tone
- 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
Briefly detail the effect of the various ions/chemicals on the local vascular tone
- 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
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
- 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
List the various reflexes that work to maintain normal arterial blood pressure
- Baroreceptor reflex2. Carotid and aortic chemoreceptors3. Atrial and pulmonary artery reflexes4. Atrial reflexes - The volume reflex
Briefly describe the baroreceptor reflex and how it helps to regulate arterial blood pressure.
- 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
Briefly describe the chemoreceptors and how they exert their effect on arterial blood pressure
- 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.
Briefly describe the atrial and pulmonary artery reflexes and how they effect changes in arterial blood pressure
- 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
Briefly describe the Bainbridge reflex
- 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
Briefly describe the CNS ischemic response
- 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
Breifly describe the Cushing Response and underlying physiological mechanism
- 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
Why is the Cushing Reflex somewhat paradoxical
- 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
Describe the potential effects of a fluid load or blood transfusion on the total peripheral resistance and arterial blood pressure
- 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
Describe the physiological response to increased salt intakeIn which circumstances is increase salt intake likely to directly affect arterial blood pressure
- 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)
What are the three major serious pathophysiological complications of chronic hypertension
- 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
Describe the regulation of renin production.What is the end goal of increased renin production
- 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
How is angiotensin II produced?
- 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
Describe the major actions of angiotensin II
- 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
How does angiotensin II directly affect an increased resorption of sodium and water
- 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
Briefly describe the pathophysiological pathway for the development of hypertension as most commonly caused by chronic renal disease
- 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
Describe the characteristic changes caused by obesity that can lead to primary hypertension
- 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
Describe the three major mechanisms by which venous return alters cardiac output in the normal heart
- 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
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
- 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
Describe how low cardiac output reduces total peripheral resistance
- 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
Describe the various conditions that can lead to a reduction in cardiac output due to reduced venous return
- 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) *
Describe the compensatory mechanisms that are elicited during acute (global) cardiac failure
- 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
Describe the potential benefits of moderate fluid retention in early heart failure
- 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
Describe the detrimental effects of fluid retention with moderate to advanced cardiac failure
- 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
Describe the vicious cycle that ensues after the onset of decompensated left sided cardiac failure
- 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
Briefly describe the flow and pressure dynamics that ensure the ductus arteriosus remains patent during foetal life and closes soon after birth
- 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.
Define circulatory shockWhat are the major causes of circulatory shock?
- 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
Describe the initial protective mechanisms induced in early hypovolaemic shock
- 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.
List the 7 major mechanisms that enable compensation following acute non-life threatening hypovolaemic shock
- 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
Describe the basic processes that occur during progressive shock
- 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
Describe the basic physiological process caused by neurogenic shockGive examples of causes of neurogenic shock
- 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
Define anaphylactic shockDescribe the physiological consequences of anaphylactic shock
- 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
Define septic shock
- 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
Describe the special features of septic shock not seen with other forms of shock
- 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
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?
- 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
What are the major wast products excreted by the kidneys, and from where are they derived?
- 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
Describe the innervation of the bladder
- 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)
Describe the neurological pathway that initiates and controls micturition
- 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
Describe the filtration unit of the kidney, the glomerulus
- 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
List the glomerular diseases that have been documented in dogs and cats
- Membranous nephropathy2. Membranoproliferative glomerulonephritis3. Proliferative glomerulonephritis4. Imunoglobulin A nephropathy5. Amyloidosis6. Hereditary Nephritis7. Minimal change disease8. Glomerulosclerosis
Describe the various pathophysiologcal processes that cause the different glomerular diseases
- 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
Describe the process whereby increased glomerular filtration of protein causes tubulointerstitial cell damage
- 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
Describe how GFR can be altered
- 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
Briefly list and describe the effects various hormones that can impact renal blood flow
- 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
What is the purpose and drive of tubuloglomerular feedback?
- 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
Describe the tubuloglomerular feedback mechanism
- 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*
Describe the physiological mechanism as to why high protein intake and hyperglycaemia increase renal blood flow and GFR
- 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
List six situations / conditions in which renal blood flow and glomerular filtration are increased
- 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
Describe the process of active transport required for sodium resorption in the renal tubule
- 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
Describe the processes that cause paradoxical aciduria with gastric outflow tract obstruction
- 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
Describe the processes that allow absorption and / or secretion in the proximal tubule
- 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
Describe the processes that allow absorption and / or secretion in the loop of Henle
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
Describe the processes that allow absorption and / or secretion in the distal convoluted tubule
- 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
Describe the processes that allow absorption and / or secretion in the late distal convoluted tubule and collecting ducts
- 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
List the various mechanisms by which tubular resorption can be controlled
- 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