Circulation

Question 1

Describe the three basic principles that underlie circulatory function

Answer 1

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 mechanism
2. 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 regulation
3. 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 2

Describe the relationship between vascular pressure and distensibility

How does this relationship affect the arterial pressure in the systemic versus pulmonary circulation

Answer 2

• 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 3

Describe vascular compliance and the relationship between compliance and vascular distensibility

Answer 3

• 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 4

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

Answer 4

• 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 pressure

Overall, an increase in vascular tone will increase the volume of blood returned to the heart and therefore cardiac output

Question 5

Describe delayed- and reverse delayed-compliance

Answer 5

• 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 6

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

Answer 6

• 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 7

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

Answer 7

• 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 8

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

Answer 8

• 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 9

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

Answer 9

• 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 10

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

Answer 10

• 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 11

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 11

The major structural difference between the various organ capillaries relates to how molecules move through the capillary wall and the underlying function of the organ

1. 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 dioxide
2. Liver: The endothelial intercellular cleft is almost wide open such that almost all plasma substances including the proteins can diffuse into the tissues
3. 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 12

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

Answer 12

• 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 13

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

Answer 13

• 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 14

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

Answer 14

• 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 15

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

Answer 15

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 valves

External 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 16

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

Answer 16

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 normal
2. 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 17

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

Answer 17

• 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 18

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

Answer 18

• 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 19

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

Answer 19

• 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 20

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

Answer 20

• 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 21

Describe the metabolism and action of nitric oxide

Answer 21

• 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 22

What are the triggers for nitric oxide release

Answer 22

• 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 23

Describe the metabolism and action of endothelin

Answer 23

• 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 24

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 24

• 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 25

Note the 4 best described vascular growth factors

Note the pathway for release of these factors

Answer 25

• 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 26

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

Answer 26

• 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 27

List the 4 most important vasoconstrictors

Answer 27

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

Question 28

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

Answer 28

• 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 29

Briefly describe the metabolism and role of bradykinin in vascular tone

Answer 29

• 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 30

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

Answer 30

1. Calcium
   
   • Increased intracellular calcium - vasoconstriction
2. Potassium
   
   • Increased intracellular potassium - vasodilatation or inhibition of vasoconstriction
3. Hydrogen ions
   
   • Increases - arteriolar dilatation
   • Decreases - arteriolar constriction
4. Magnesium
   
   • Increases inhibit smooth muscle contraction
     
     • Powerful vasodilation
5. Anions - acetate and citrate
   
   • Mild degrees of vasodilation
6. 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 31

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 31

1. Arteriolar constriction
   
   • increased total peripheral resistance and increase in mean arterial blood pressure
2. 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 output
3. Direct stimulation of the heart
   
   • Increases in both rate and force of contraction
   • Increased cardiac output

Question 32

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

Answer 32

1. Baroreceptor reflex
2. Carotid and aortic chemoreceptors
3. Atrial and pulmonary artery reflexes
4. Atrial reflexes - The volume reflex

Question 33

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

Answer 33

• 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 34

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

Answer 34

• 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 35

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

Answer 35

• 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 36

Briefly describe the Bainbridge reflex

Answer 36

• 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 37

Briefly describe the CNS ischemic response

Answer 37

• 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 38

Breifly describe the Cushing Response and underlying physiological mechanism

Answer 38

• 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 39

Why is the Cushing Reflex somewhat paradoxical

Answer 39

• 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 40

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

Answer 40

• 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 41

Describe the physiological response to increased salt intake

In which circumstances is increase salt intake likely to directly affect arterial blood pressure

Answer 41

• 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 42

What are the three major serious pathophysiological complications of chronic hypertension

Answer 42

• 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 43

Describe the regulation of renin production.

What is the end goal of increased renin production

Answer 43

• 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 44

How is angiotensin II produced?

Answer 44

• 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 45

Describe the major actions of angiotensin II

Answer 45

• 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 46

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

Answer 46

• 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 47

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

Answer 47

• 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 48

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

Answer 48

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 output
2. 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 apnoea
3. Angiotensin II levels become increased
   
   • Likely primarily due to increased SNS activity
   • Leads to increased aldosterone also
4. 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 49

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

Answer 49

1. Increased venous return to the right atrium alters output by Frank-Starling law of the heart
   
   • Increased stretch leads to increased force of contraction
2. Sinus node stretch
   
   • Stretching of the SA node increases the automaticity of the node due to more rapid changes in membrane polarity
   • Increased heart rate
3. 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 50

Describe the process by which a descrease in total peripheral resistance causes an increase in cardiac output

Note examples of clinical conditions that cause a reduction in TPR

Answer 50

• 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 51

Describe how low cardiac output reduces total peripheral resistance

Answer 51

• 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 52

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

Answer 52

• 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 53

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

Answer 53

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 return
2. 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 54

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

Answer 54

• 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 55

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

Answer 55

• 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 56

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

Answer 56

• 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 57

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

Answer 57

• 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 58

Define circulatory shock

What are the major causes of circulatory shock?

Answer 58

• 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 59

Describe the initial protective mechanisms induced in early hypovolaemic shock

Answer 59

• 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 60

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

Answer 60

1. Baroreceptor reflex
   
   • SNS stimulation
2. Central nervous system ischaemic response
   
   • powerful SNS activation, but not elicited in mild cases of shock
3. Reverse stress-relaxation
   
   • arteriolar smooth muscles slowly contract to reduce capacitance and ensure adequate filtration pressure at the capillary
4. Increased secretion of renin - activation of the RAAS
   
   • Decreases salt and water loss
5. Secretion of ADH / vasopressin
   
   • Vasoconstriction and greatly enhances water resoprtion in the renal collecting duct
6. Increase secretion of NE and epinephrine by the adrenal
   
   • Augments the SNS effects
7. Other compensatory mechanisms
   
   • Resorb fluid from the interstitial space
   • Resorb fluid from the GIT
   • Increased thirst and salt appetite

Question 61

Describe the basic processes that occur during progressive shock

Answer 61

• 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 62

Describe the basic physiological process caused by neurogenic shock

Give examples of causes of neurogenic shock

Answer 62

• 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 63

Define anaphylactic shock

Describe the physiological consequences of anaphylactic shock

Answer 63

• 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 64

Define septic shock

Answer 64

• 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 65

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

Answer 65

1. High fever
2. Marked vasodilation
3. High cardiac output
   
   • Increased metabolic demand and arteriolar dilatation (autoregulatory mechanism)
   • Bacterial or endotoxin stimulation of cellular metabolism
4. Sludging of blood and auto-agglutination
   
   • Seen earlier with septic shock than in other forms
5. Development of DIC
   
   • May lead to widespread intra-tissue haemorrhage