CB Quiz 2 Flashcards
What enzyme is mainly responsible for Cholesterol Synthesis
Acetyl Coenzyme A (Acetyl CoA)
What is the main source of transport for Cholesterol?
How is it taken up in cells?
LDLs
Specific surface receptors
Describe the Structure of Cholesterol
Made up of a steroid nucleus with a condensed 4 ring structure
Attached to a hydrocarbon chain
Low H2O solubility
Explain the full Process of Cholesterol Synthesis
Cholesterol is synthesized from Acetyl CoA enzyme in 3 stages
- Synthesis of Isopentenyl Pyrophosphate from Mevalonate (in 3 consecutive reactions requiring ATP)
- Condensation of six molecules of Isopentenyl Pyrophosphate to form Squalene (C5 -> C10 -> C15 - C30)
- Squalene cyclizes and the tetracyclic product is converted to cholesterol (first changes to Squalene 2,3-epoxide, which undergoes cyclization to form Lanosterol which is then converted to Cholesterol by multiple reactions)
=> Mevalonate -> Isopentenyl -> Squalene ->Squalene 2,3-epoxide -> Lanosterol -> Cholesterol
What’re the 2 main ways cholesterol can be obtained
Diet (Exogenous)
Synthesized in the body (Endogenous)
Endogenous
Synthesized in the body
Exogenous
Obtained in diet
What are the major sites of cholesterol synthesis? Can it, generally speaking, be produced in any cell?
All nucleated cells are capable of synthesis but the major sites are the Liver, Intestine, Reproductive Tissue, and Adrenal Glands.
So no, not every cell… every nucleated cell lmao
Statins
Class of drugs that inhibit cholesterol Synthesis
Brownie points: Inhibits HMG CoA Reductase
LEARNING OUTCOME: Describe the Physiological Regulation of Cholesterol in the body
The rate of cholesterol formation in the body is highly responsive to cellular levels of cholesterol. This is controlled by the negative feedback mechanism mediated primarily by changes in its amount in the body and the activity of
3-Hydroxy-3-Methylglutaryl CoA Reductase (HMG CoA Reductase) which is inhibited by Statins.
Control of HMG CoA Reductase:
• Rate of Synthesis of Reductase mRNA is controlled by the sterol regulatory element binding protein (SREBP). When cholesterol levels are low, this transcription factor induces transcription of HMG CoA Reductase.
• Rate of Translation of Reductase mRNA is inhibited by Nonsterol Metabolites derived from Mevalonate and dietary cholesterol.
• Degredation of the Reductase due to increased levels of cholesterol.
• Phosphorylation decreases the activity of the Reductase in response to low levels of ATP
LEARNING OUTCOME: Describe the Pharmacological Regulation of Cholesterol
Pharmacological Regulation of Cholesterol:
1. Statins: Inhibition of in vivo synthesis of cholesterol in the liver (by inhibiting HMGCoA Reductase)
2. Cholestyramine/Colestipol: Reduces Bile Acids in the intestine which reduces absorption of Exogenous cholesterol and increases the metabolism of Endogenous cholesterol into bile acids
3. PCSK9 Inhibitors: Reduces circulating LDL. PCSK9 enhances the number of LDL receptors across tissues (given to patients intolerant of Statin)
These methods proved to decrease cardiovascular-related mortality among patients with high LDL presence in their blood.
Describe the role of the drug Colestipole
Reduces Bile Acids in the Intestines which reduces absorption of Exogenous cholesterol and increases the metabolism of Endogenous Cholesterol into bile acids
What is the Role of PCSK9?
PCSK9 enhances the number of LDL Receptors across tissues
When are PCDK9 inhibitors prescribed?
When the patient is intolerant of Statin
What are the main derivatives of Cholesterol?
Bile Acids
Bile Salts
Steroid Hormones
Vitamin D
What is the significance of Bile Salts and Bile Acids in terms of cholesterol regulation.
Their production eliminates cholesterol from the body by converting it into Bile
Where is Bile synthesized
Liver
Where is bile stored and secreted? Where is it secreted to?
Stored in the gall-bladder
Secreted through the bile duct
Secreted into the small intestine (Duodenum)
What is the primary function of Bile Acids
Bile acids are amphipathic molecules which allows them to emulsify triglycerides in the small itnestine
How are Bile Salts produced?
What is their main function?
What happens when bile salts are exposed to the Bacterial Flora of the intestine
Produced in the liver, bile salts are made through conjugating bile acids with either Glycine or Taurine.
The main function of Bile Salt is being a detergent
When Bile Salts are exposed to Bacterial Flora of the intestine:
- Aids in the regeneration of Bile Acids (from the removal of glycine or Taurine) and production of Secondary Bile Salts (removal of OH group)
What is Cholelithiases?
How is it treated?
Occurs due to lack of bole salts being secreted to handle the amount of cholesterol present. It is caused by either:
malabsorption of bile acids
Biliary tract obstruction
Lack of Melatonin
This condition results in cholesterol precipitates in the Gall-Bladder
Cholecystectomy is the removal of the gall bladder (Treatment)
What are the steroid hormones that are derived from Cholesterol?
Progesterone Androgens Estrogens Glucocorticoids Mineralocorticoids
Progesterone
Prepares the lining of the uterus for implantation of an ovum and maintenance of pregnancy
Androgens
Responsible of the development of male characteristics
Estrogens
Responsible for the development of female secondary characteristics as well as participation in the ovarian cycle
Glucocorticoids
Promote Gluconeogenesis and breakdown of glycogen, Enhances segregation of Fat and protein, and inhibits inflammatory response
Gluconeogenesis
Production of glucose and eventually glycogen
Mineralocorticoids
Aldosterone:
Or Anti-diuretic hormone
Acts on distal tubules of the kidney to increase reabsorption of Na+ along with the excretion of K+ and H+
How is Vitamin D synthesized?
Cholesterol is photolysed bu UV light to pre-vitamin D3 which spontaneously isomerizes into Vitamin D3 which is converted to Calcitol, the active hormone which produced Vitamin D
What are the functions of Vitamin D
Vitamin D binds to intracellular receptors and selectively stimulates gene transcription.
Also Regulates plasma levels of Calcium and Phosphorus
What are the diseases associated with vitamin D
Vitamin D deficiency in children causes Rickets which is characterized by inadequate calcification of cartilage and bone.
Vitamin D deficiency in Adults leads to the softening and weakening of bones which is called Osteomalacia.
What is the primary function of blood flow?
Delivery of O2, nutrients, and water as well as the removal of metabolic waste from tissues and cells
What is Ohm’s law in relation to blood flow?
(DeltaP) = Flow (Q) x Resistance (R) or DeltaP = QR
Darcy’s Law
Darcy’s Law: Q = DeltaP/R => Flow varies proportionately with pressure gradient and inversely proportionately with resistance
How do we measure Cardiac Output CO?
CO = HR x SV
Heart rate x stroke volume
AND
CO = MAP/TPR where CO is the cardiac output, MAP is the mean arterial pressure, and TPR is the total peripheral resistance. Therefore, a circulation with low resistance does not require a high pressure to maintain flow
Equation for Vascular Resistance
Vascular Resistance: R = nL/r^4. R is resistance, n is viscosity, L is length, r is the vessel radius
When is pressure in the heart generated
During systole
What is the relation between CO and Systolic Pressure
As CO increases, Systolic pressure increases
What is the vascular tree and how does pressure vary between them?
• Pressure drops across the vascular tree (Aorta > Capillaries > Great Veins
What is the relation between changes in vessel diameter and resistance
small changes in vessel diameter have large effects on resistance and hence flow R = 1/r^4
As the radius increases, resistance decreases dramatically
What is the relation between Flow Q and vessel radius
Flow (Q) is proportional to the 4th power of the radius
What is the relation between viscosity n and Flow Q as well as resistance R
Viscosity is proportional to resistance and inversely proportional to flow as resistance is inversely related to flow.
WhaWhat are the Factors affecting viscosity?
- Concentration and type of plasma protein
- Hematocrit (The proportion of blood volume occupied by red cells). Anemia would decrease and Polycythemia would increase viscosity
What is Axial Accumulation and it’s effects on hematocrit levels in capillaries?
• Capillaries and smaller vessels tend to have slightly lower hematocrit due to Axial Accumulation (Red cells are in the center of the flow so branches get relatively more plasma to red cell
What tends to affect flow more?
Viscosity or Radius and why?
• Radius has much more effect on flow than viscosity (r^4)
What is Laminar Flow and its association with Shear Stress in blood vessels
- Laminar Flow: Viscosity of blood causes Laminar Flow. At the sides of the vessel, the flow is lowest as blood pulls on the vessel wall. This is Shear Stress => increasing flow increases shear => Slowest flow is this outer later which slows the flow in the next layer => the highest velocity is at the center. Note that Laminar Flow is silent.
- Small arteries have a large area to volume ratio => most blood is near the wall => increased viscosity slows flow. In larger arteries, there are more layers and so there is increased velocity
Describe the Relationship between Cross Sectional Area and Flow Velocity
• Cross Sectional Area & Flow: In a closed system, the volume of blood flowing should be constant => Cardiac Output = Venous Return. Flow (Q) = Area (A) x Flow Velocity (V). Since size varies through circulation, but flow is constant, flow velocity varies with size. With a large area, the flow velocity in capillaries is much slower than in both veins and arteries
What is Non-Laminar Flow and under normal conditions, where can we find this flow.
• Non-Laminar Flow: At high velocities (or at large diameters), flow can become turbulent. Under normal conditions, non-laminar flow tends to occur in the ascending aorta and around branch points (narrowed points where velocity increases). Unlike laminar flow, turbulent flow is not silent
What is Transmural Pressure?
Transmural Pressure: Pressure that either distends (swells) or collapses blood vessels. It is the difference in pressure across the wall where PTM = Pi - Po. Pi is pressure inside and Po is the pressure outside. If Po > Pi, then the vessel will collapse
What is the Law of LaPlace and answer the following questions:
How does wall tension increase
How does this law apply in Capillaries and small vessels
How does this law apply in large arteries
How does this law apply in large Veins
The Law of LaPlace: The Transmural Pressure (PTM) is related to the wall tension and the radius where PTM = T/R where T is tension and r is radius or T = PTM x R => wall tension increases with radius and PTM. Wall tension can be thought of as how thick the vessel wall needs to be. For small vessels such as capillaries, they have a small radius and hence less wall tension is required to balance out the dissenting pressure => Thin walls. For vessels with a larger radius, more wall tension is required to balance the distending pressure and hence why a Dilated Aneurysm (Dilated Aorta) is more likely to rupture. Arteries are more likely to rupture when compared to veins due to the decreased pressure in veins
Dilated Aneurysm
Dilated Aorta or other Large arteries.
What is Distensibility and Compliance?
How does this differentiate Arteries and Veins
Distensibility is the ability of a vessel to change in volume compared to pressure.
Distensibility and Compliance: Veins are much more distensible than arteries due to their ability to expand and swell. Compliance is the change in volume for a given change in pressure where DeltaV = C x DeltaP. Since veins have a larger volume as well as a greater Distensibility, they have a lot more compliance which allows them to be a reservoir for blood
Describe the Structure of Arteries and Arterioles
Arteries and Arterioles:
Arteries have a thick layer of Smooth Muscle which allows them to withstand high pressures.
Elastin Fibers provide elasticity. As blood is ejected, the aorta expands and the rebound in diastole propels the blood onward.
Collagen Fibers provide strength
What is the relation between the abundance of Collagen and Elastin in arteries and arterioles and their size
Collagen and Elastin Fibers decrease in abundance as arteries and arterioles get smaller
What is the relationship between Age and Blood Pressure
As we get older, vessels get stiffer and less compliant which is one of the factors pertaining to high blood pressure in older patients
What are Arterial Pulses and how do they differ across different arterial sizes
Compliance of large arteries evens out flow so that it occurs through the whole cardiac cycle. In large arteries, flow is pulsatile but in smaller ones like arterioles and capillaries compliance has reduced the pulsations and flow is mainly continuous. The Pressure Pulse Wave (PPW) is created by systolic ejections and travels much faster than blood. An increased PPW is a Parker of increased arterial stiffness and cardiovascular morbidity
Describe the Structure of small arteries and arterioles
Arterioles have a thick layer of smooth muscle. There are less Elastin and Collagen Fibers making them less compliant compared to larger arteries. These are the sites of total peripheral resistance.
What is Vascular tone?
How is it Regulated?
What are it’s effects on Resistance and Flow
Vascular Tone: Vascular Tone is the level of constriction applied across vessels. Arteries at rest are slightly constricted meaning they can both constriction and dilate. Constriction decreases radius => increases resistance => decreased flow and vice versa. Arterial tone is the balance of constrictors and dilators that are acting on the vascular smooth muscle!!!
How does the body regulate where blood flow should be prioritized
In small arteries and arterioles, the vascular tone increases or decreases constriction and hence resistance (inversely to constriction). Blood always takes the path of least resistance. Smooth muscles aid in this constriction. When the body relaxes those muscles along a certain path, it dilates the vessel allowing it to be less resistant and hence more blood flow.
How is Vascular tone regulated (in general) and what are the 3 levels
Regulation of Vascular Tone: Vascular tone responds to both Intrinsic (local) and Extrinsic (systemic) factrors. Each vascular bed behaves slightly different and varies in the use of intrinsic and extrinsic control. They can be split into 3 levels:
- Mechanical Stimuli: Stretch and Shear (Intrinsic)
- Endothelial Regulation: Work along with other metabolites and Autocoids in response to local demand (intrinsic)
- Systemic Regulation: Nerves and Hormones (Extrinsic)
What is the Myogenic Response?
Is it intrinsic or Extrinsic
The Myogenic Response: Smooth muscle contracts when stretched. Occurs in most smooth muscles including vascular muscles due to opening of Ca2+ channels. It occurs in a number of vascular beds including coronary and renal. This response contributes to the Basil Tone (tone at rest) of arteries and stabilizes flow preventing Excessive Perfusion (movement of fluid through the circulatory system). This is an important feature of autoregulation
Intrinsic
What is Perfusion?
Movement of Fluid through the circulatory system
What is a paracrine response
When a cell produces a signal to induce changes in nearby cells.
Describe the Endothelial Regulation of Vascular Tone
Endothelial Regulation: Work along with other metabolites and Autocoids in response to local demand (intrinsic
The Vascular Endothelium performs its functions through the release of Paracrine Factors (when a cell produces a signal to induce changes in nearby cells). Some are dilators such as Nitric Oxide (NO) and Prostacyclin (PGI2) while others are Vasoconstrictors (constrictors) such as Endothelins (ET).
Nitric Oxide: It is a free radical that dilates the vascular endothelium, replacing smooth muscle. Production is increased by shear stress or other agents. It is Anti-Thrombogenic (Prevents blood clots) and Anti-Atherogenic (Prevents formation of fatty deposits in arteries). An unhealthy endothelium causes Endothelial Dysfunction which is the primary step of Atherosclerosis and cardiovascular disease.
Metabolites and Other Autocoids: Normal metabolism of cells produces waste products in the blood stream. Increased amounts of these products and decreased amounts of O2 in the blood promote vasodilation. Substances such as histamine are also Vasoactive causing dilations and constrictions. Various other agents that are produced by cells locally tend to be pathological and may cause inflammation. Vasodilation usually occurs to increase blood flow which helps flush out accumulated metabolites
Describe the Extrinsic regulation of Vascular Tone
Systemic Regulation: Nerves and Hormones (Extrinsic)
The sympathetic nervous system is responsible for the maintenance of vascular tone. Most arteries are innervated by sympathetic fibers where increased sympathetic activity will increase vasoconstriction. An example is constriction due to Noradrenaline acting at a1-Adrenoceptors. Beta-Adrenoceptors are also on arteries but lead to dilation. These are prevalent in the skeletal muscle vascular beds
List the Systemic and Pulmonary Arterial Pressure Values
Systemic Arterial Pressure: 120/80 mmHg
Pulmonary Arterial Pressure: 25/10 mmHg
Define Hypertension along with its risk factors
Hypertension: It is consistent readings with a systolic pressure of over 140mmHg or diastolic over 90mmHg (Grade 1). Uncontrolled hypertension is a major risk factor for cardiovascular disease and renal disease
What are Baroreceptors and where are they found
Baroreceptors sense the rate of rise in pressure and the magnitude of pressure. As arterial pressure increases, so does the Baroreceptor firing rate
Baroreceptor Reflex:
- Sensory Afferents: The Baroreceptors in the walls of the Aortic Arc and Carotid Sinus.
- Central Relays: Cardiovascular Centers in the brain stem
- Effector Efferents: Innervating the Heart and Blood Vessels
What is the Cardiovascular Control Center and explain briefly the role of each part
Cardiovascular Control Center:
The Medulla is the primary site for regulating sympathetic and parasympathetic outflow.
The NTS receives sensory input from different receptors.
The Hypothalamus modify the activity of the Medullary Centers
Explain how rising blood pressure ends up with the fall of the MABP (mean arterial blood pressure)
List the Steps Briefly
Overview: Rising blood pressure, increases firing of Baroreceptors to the NTS => Decrease in sympathetic output and increase in vagal activity (PNS) => Decrease in SNS-induced vascular tone (Reduction in TPR) => Rapid decrease in heart rate and reduction in cardiac contractility reducing Cardiac Output (CO) => Reduction in CO and TPS leads to fall in MABP or mean arterial blood pressure.
Explain this blood pressure is measured (no need to include everything in the response)
Measuring Blood Pressure: Blood pressure is a continuous variable. Measurement can be direct (Arterial Catheter or Implanted Sensor) or indirect (Cuff with stethoscope or sensor). Normal BP varies with age, sex, race, etc… and varies over the course of months and even throughout the day
What is the relation between age and BP
Blood pressure increases with age due to arterial stiffening. Heart Rate does not change with age but exercise tolerance does (Max HR
What is the main function of capillaries?
Capillaries are the site of nutrient exchange
Describe the structure of capillaries
Capillaries are composed of a single layer of endothelial cells with some pericytes. They have thin walls and a large surface area to maximize diffusion
What are the different types of capillaries?
What is the main difference between them?
Give an example as to where to find each type.
• There are 3 types of capillaries which depend on the closeness of endothelial cells to each other
◦ Continuous: Slow diffusion of small lipophobic molecules and very fast diffusion of gasses and lipophilic molecules
‣ Found almost everywhere
◦ Fenestrated: Small lipophobic molecules
‣ Found in Kidneys
◦ Sinusoidal or Discontinuous: Large lipophobic molecules
‣ Found in Liver
Describe the variables and relations found in Fick’s Law
Transport and Fick: Fick’s Law states that the rate of diffusion (Js) is independent on 4 variables where Js is:
• Proportional to concentration gradient (Delta C)
• Inversely proportional to diffusion distance (Delta x)
• Proportional to the surface area available (A)
• Proportional to the solute diffusivity (property depending on size, solubility etc…) (D)
• Js = -D x A x dC/ dx
How do lipids cross the membrane
Directly across the membrane through normal diffusion
How do water-soluble substances cross the membrane?
Intercellular pores
Are solute properties and gradients likely to change in terms of capillaries? Are there any exceptions?
• Solute properties and gradients are unlikely to change except through Capillary Recruitment (Increased Capillaries)
What is Oncotic Pressure
• Oncotic (or Colloid Osmotic Pressure) is due to plasma proteins (mostly albumin) that do not move between fluid compartments unlike electrolytes hence they remain in the vascular compartment and hold fluid there
What is Hydrostatic Pressure
Pressure exerted by a fluid at equilibrium
Fluid Flow out of the capillary depends on
◦ Oncotic Pressure (Osmotic pressure induced by proteins, mostly albumin) in the capillary and Interstitium
◦ Hydrostatic Pressure (Pressure exerted by a fluid at equilibrium) in the capillary and in tissue
Net filtration pressure is determined by what variables?
• Net Filtration Pressure = (Pc-Pi) - (pc - pi)
◦ Pc is pressure in capillary
◦ Pi is pressure outside capillary (Interstitum)
◦ .pc is oncotic pressure in capillary
◦ .pi is onconic pressure outside capillary (Interstitum
Describe the structure and function of Veins highlighting two differences between veins and arteries.
• Veins carry blood from capillaries back to the heart at the right atrium
• Structurally, veins are very similar to arteries but have much thinner walls
◦ Very little smooth muscle but are still capable of constricting (Venous Tone)
‣ Constriction is innervated by SNS fibers (Noradrenaline on a1-adrenoceptors)
‣ Constriction increases pressure and decreases venous capacitance (ability to store) which would redistribute the blood
◦ Small amounts of collagen and elastin
• The venous system is a low pressure system which allows it to have thinner walls (LaPlace)
• Their Distensibility gives veins the ability to store blood.
◦ 2/3 of the blood volume is held in the venous system.
◦ 20x compliance of arteries
Will an increase in venous return lead to an increase in cardiac output?
Yes
What are the factors that affect venous return?
• Venous return is altered by ◦ Venous Pressure/Venoconstriction ‣ During diastole, the right atrial pressure drops to 0 hence increasing the pressure gradient and increasing flow ◦ Skeletal muscle and Thoracic Pumps ◦ Gravity
When in Supine position, what effect does it have on venous return?
Increase
How does venous return vary around the body
• Venous pressure (hydrostatic pressure) increases as you go below the heart and decreases above (negative in the brain)
What is Transmural Pressure
Difference in pressure between two sides of a wall
What is the effect of Transmural pressure on venous pooling.
◦ The increased Transmural Pressure (Difference in pressure between two sides of a wall) distends the veins causing venous pooling
‣ That does not mean that flow stops
‣ Due to their Distensibility, the veins expands and venous return temporarily decreases
What structural capability of veins allows for the movement of blood from the legs to the heart?
◦ Valves, muscle, and thoracic pump (breathing) breaks the column into smaller sections aiding return
‣ Failure of valves or muscle movement decreases return and increases venous pooling and Oedema (Tissue swelling due to excessive fluid retention and buildup
Discuss Postural Hypotension
• Postural Hypotension: On standing, the effect of gravity is venous pooling and a drop in venous return whereas when supine, blood in the legs is leveled with the heart.
◦ Cardiac Output and hence blood pressure falls triggering the Baroreceptor reflex which increases vasoconstriction, heart rate, and contractility
◦ Effects are imperceptible (slight/gradual
LEARNING OUTCOME: Discuss factors affecting Venous Return and expand on the effects of gravity on venous return
Venous Return:
• Increasing venous return will increase cardiac output (CB12)
• Venous return is altered by
◦ Venous Pressure/Venoconstriction
‣ During diastole, the right atrial pressure drops to 0 hence increasing the pressure gradient and increasing flow
◦ Skeletal muscle and Thoracic Pumps
◦ Gravity
Gravity:
• Blood pumping upwards has to work against gravity which is a negative factor for venous return.
◦ In the Supine Position, venous return is increased.
• Venous pressure (hydrostatic pressure) increases as you go below the heart and decreases above (negative in the brain)
◦ This allows blood to move upwards against gravity.
◦ Venous structure prevents the collapse of veins (compliance)
◦ The increased Transmural Pressure (Difference in pressure between two sides of a wall) distends the veins causing venous pooling
‣ That does not mean that flow stops
‣ Due to their Distensibility, the veins expands and venous return temporarily decreases
◦ Valves, muscle, and thoracic pump (breathing) breaks the column into smaller sections aiding return
‣ Failure of valves or muscle movement decreases return and increases venous pooling and Oedema (Tissue swelling due to excessive fluid retention and buildup
• Postural Hypotension: On standing, the effect of gravity is venous pooling and a drop in venous return whereas when supine, blood in the legs is leveled with the heart.
◦ Cardiac Output and hence blood pressure falls triggering the Baroreceptor reflex which increases vasoconstriction, heart rate, and contractility
◦ Effects are imperceptible (slight/gradual)
Define the 2 ways to measure venous pressure
Venous Pressure:
• The Central Venous Pressure (CVP) measures right atrial pressure via Catheter (medical device) in the central vein.
◦ It reflects the venous return and cardiac function
◦ Can be used to assess fluid volume in fluid replacement
◦ CVP increases in heart failure due to volume expansion
• The Jugular Venous Pressure (JVP) is seen in the internal jugular vein of a sitting patient
◦ It is an indirect measure of CVP
◦ The Internal Jugular Veins fill from above
◦ The Sternal Angle is the Zero Point. More than 3 cm above is abnormal
◦ A raised JVP suggests an increase in right arterial pressure
What is the Hepatic portal vein responsible for
- The Hepatic Portal Vein carries blood from the gastro-intestinal tract to the liver
- All substances absorbed from the intestines pass through the liver including drugs
What is the significance of capillaries found in the Hepatic portal vein
• Capillaries in the liver are sinusoidal
◦ Large gaps allow large substances to be absorbed
Describe the effects of Cirrhosis on the Hepatic Portal Vein
• In liver diseases such as Cirrhosis, resistance in the hepatic portal system increases
◦ This causes flow pressure to increase to maintain flow
◦ This increased pressure gives the portal hypertension
◦ High portal pressures lead to Shunt Vessels which bypass the liver back into the Systemic Venous System.
◦ Given the liver’s role in Metabolism and Detoxification, this leads to morbidity where bleeding abnormalities and toxins damages other organs. The most common are Hepatorenal and Hepatopulmonary Syndromes.
Explain the function of Lymphatics and it’s relation to Oedema.
Lymphatics and Drainage:
• The fluid leaving capillaries is cleared by the lymphatic circulation carrying fluid, protein, and large molecules from the interstitium
• The lymphatic vessels have a rhythmical smooth muscle contraction creating negative pressure in the interstitium
• Plasma Flows through capillary beds -> Net movement of water from capillaries into interstitial space -> Interstitial fluid entering lymph capillaries -> 50% of lymph returned to circulation at subclavian veins and other 50% reabsorbed back into circulation at lymph nodes.
Oedema:
• Oedema is the collection of fluid in the interstitium not removed by the lymphs due to increase movement of fluid out of vascular compartment or drop in removal by lymph
• Caused by:
◦ Increased hydrostatic pressure or Venous Pooling
◦ Decreased Oncotic Pressure due to loss of plasma proteins causing a decreased pressure holding fluid in
◦ Increase capillary membrane permeability which increased flux of fluid out
◦ Lymphatic Obstruction removing it’s function
What is Perfusion
Passage of Fluid through the circulatory or lymphatic system
What is the relation between flow and vascular tone
• Flow takes the path of least resistance so altering vascular tone drives local perfusion (R = 1/r^4)
What is the structure of Vascular beds
Parallel
Briefly explain the effect of Intrinsic and Extrinsic factors on the Vascular tone’s response. Explain how it’s important during exercise.
• Vascular tone responds to both intrinsic and extrinsic factors
◦ Each vascular bed behaves slightly differently and hence vary in the use of intrinsic and extrinsic control
◦ Vascular beds are parallel
◦ During exercise, Vascular beds of the heart and skeletal muscles increase in size decreasing resistance and increasing flow
‣ This is done by altering the resistance of each bed to facilitate flow to where it is needed.
◦ Primarily intrinsic stimuli such as stretch and shear as well as endothelial regulation and metabolism regulate flow
• Demand is highest in the Skeletal muscle
• Perfusion of some vascular beds are more important than others and hence are protected primarily during a challenge
How is the Circulatory system controlled in general
Autoregulation
What is the primary role of coronary arteries?
Where do coronary arteries drain?
• The coronary arteries (left and right) supply the myocardium and drain in the right atrium
What is Ischemia?
Restriction of blood supply in tissues
What is the major problem with coronary arteries?
• Most of these arteries are end-arteries but there are some collaterals between arterioles.
◦ This indicates that there is only one way to supply blood to the myocardium and hence a blockage is devastating
◦ There is a high demand of O2 which increases the risk of Ischemia (restriction of blood supply in tissues)
How Does coronary blood flow change throughout the cardiac cycle?
• The heart has a high basal O2 consumption and receives 5% of cardiac output even at rest
◦ Greater than 65% O2 Extraction at rest
◦ Increased activity must be met by an increased perfusion
What is Hypoxia
A condition in the body where lack of O2 supply is present due to constriction => dilation required to meet increased demand.
Dilation in lungs => constriction needed
What are the Coronary Adaptations that enhances and regulates heart function
Coronary Adaptations:
• The heart has a high capillary to Myocytes density
◦ This decreases diffusion distance
◦ Has a large amount of myoglobin which counteracts the impact of systole (providing oxygen when there is no supply)
• Control of this circulation is mostly Intrinsic Metabolite Induced
◦ Increased work by myocytes increases the amount of K+ and H+
◦ Working muscle use ATP so more adenosine (Hypoxia, a condition in the body where lack of O2 supply is present due to constriction)
◦ Increased flow leads to more NO (Causes vascular dilation) via shear stress (NO usually released in greater quantity through Shear Stress)
• Extrinsic effects are done through the SNS
◦ The coronary arteries have lots of B-adrenoceptors which means SNS actions both constrict and dilate
◦ Other SNS actions increase heart work
What is the main function of the Circle of Willis
It allows for perfusion if one artery is blocked or affected.
Describe how Cerebral Perfusion is measured
• Cerebral Perfusion is measured by CPP = MAP - ICP
◦ MAP is the mean arterial pressure
◦ ICP is the Intracranial Pressure (Pressure within the skull) Raised ICP is a sign of a tumor or Oedema
Explain how Cerebral Blood Flow is Measured
• Cerebral Blood Flow is measured by CBF = CPP/CVR (Similar to Q = DeltaP/R)
◦ CVR is Cerebral Vascular Resistance
◦ CPP is Cerebral Perfusion
Blood Flow is maintained by constriction and dilation in response to challenges. What can cerebral vessels work best with? Constriction or dilation?
Constriction since it deals with high pressure better than low pressures
Describe the Cerebral Structural Adaptations
Cerebral Structural Adaptations:
• Anastomosis (Connection between 2 branches/arteries) of major arteries in the Circle of Willis and high capillary density
◦ There is more vascular tissue in the cranium than neural tissue
• Neurovascular Coupling
◦ Nerve firing linked to vasoactive K+, adenosine, and NO
◦ This is the basis of functional MRI (fMRI) since it measures blood perfusion
• SNS Fibers present but lack of a1-Adrenoceptors limit response thus brain is not affected by Baroreceptor activation
◦ PNS releasing ACh (acetylcholine) and VIP may contribute to vasodilation
Discuss Cerebral Autoregulation
Cerebral Autoregulation:
• The primary control of autoregulation is via Myogenic activity and those of local mediators
• Cerebral arteries will contract when stretched
◦ Constricting due to increased pressure, increases resistance, limiting blood flow
• Hypoxia, O2, and Metabolism: Activity linked to K+, adenosine, and NO (Neurovascular coupling above).
◦ At low PaO2 (Pressure of oxygen in arteries), there is an increase in cerebral blood flow involving NO and local adenosine release leading to dilation of the vessels
◦ More systemic hypoxia is impacted by ventilation of PaCO2 (Pressure of CO2 in arteries)
◦ CO2 is a cerebral dilator acting via NO
◦ Low Ph (=> high H+) is also a cerebral dilator since H+ tends to relax muscle
• Hypocapnia (Low CO2): Leads to constriction and poor perfusion
What are the effects of Hypoxia and Hypocapnia on Cerebral blood flow. Explain briefly
Hypoxia will lead to an increase due to dilation with metabolites releasing NO.
Hypocapnia leads to constriction and poor diffusion due to low CO2 levels
Hypoxia is a straight linear line whereas hypocapnia has the same shape as Normocapnia but just lower
What are the Cereberal challenges and state the mechanisms in place to respond
Cerebral Challenges:
• Vascular Dilation (Headaches/migraine)
• Postural Hypotention: Transient fall in cerebral perfusion on standing
◦ Usually prevented by baroreflex
◦ Indicative of dehydration
• Cerebrovascular Accidents: Strokes by Vasospasm (too much contraction) or atherosclerosis
• Changes to Intracranial Pressure: Due to Oedema
Mechanisms:
Cerebral Ischemic Response
Cushing Reflex
Describe the Ischemic Response
Cerebral Ischemic Response:
• The cerebral Ischemic Response redistributes blood to the brain
• Falling arterial pressure leads to sympathetic vasoconstriction from Baroreceptor reflex
◦ Resistance increases systemically but since the brain has few SNS receptors, there is no increase in cerebral resistance
◦ Blood is hence redistributed away from the periphery to the brain (Path of least resistance
Describe the Cushing Reflex and the main issue arising from it
Cushing Reflex:
• The skull is rigid => if brain volume increases, then so done Intracranial Pressure (ICP).
◦ The Cushing Reflex decreases perfusion pressure and contracts cerebral vessels
• The resultant Ischemia (From Cushing Reflex) will lead to increased sympathetic constriction increasing blood pressure
◦ Increased pressure triggers a Baroreceptor-mediated Bradycardia (Low heart rate)
◦ Increasing cerebral perfusion, increases pressure leading to further increases in ICP or Oedema (Creates cycle of competing feedback loops)
List the main steps int he vicious cycle between Ischemia and Cushing, taking into account the Cerebral Ischemic Response
Basically Give an overview of the cycle
Overview of Cycle: Ischemia is due to low blood perfusion in brain -> Baroreceptor reflex increases sympathetic vasoconstriction -> Few SNS receptors in brain => Increased Perfusion -> Too much perfusion => Cushing reflex causes cerebral constriction to occur -> Ischemia …
What does the Splanchnic Circulation supply?
Liver and GI
What are the effects of the following on Splanchnic Circulation:
- Food Digestion
- Sympathetically active states (Exercise or Fight/flight)
- Hemorrhage/shock
- Blood flow increases with food digestion due to extrinsic hormonal control which can double GI blood flow
- In Sympathetically Active states (Exercise, fight/flight), vasoconstriction redistributes blood from GI tract to heart and muscle
- In Hemorrhage (Shock), prolonged redistribution leads to the Necrosis (Death of body tissue) of microvilli
What is Columbus’s Podcast
SOTON BRAIN HUB PODCAST
What are the two blood supplies to the lungs
Bronchial and Pulmonary Circulation
Briefly describe Bronchial circulation
• The bronchial circulation is a systemic circulation arising form the aorta
• Supplied oxygen and nutrients to the smooth muscle and interstitial tissues
• The bronchial circulation drains into the pulmonary veins and returns back to the left ventricle
◦ => Venous return is slightly greater than cardiac output
Describe the path of pulmonary circulation, comparing pressure and Cardiac output to the systemic circulation.
Pulmonary Circulation:
• The Pulmonary circulation transports deoxygenated blood from the right ventricle to the alveolar capillaries and returns oxygenated blood to the left atrium
• Pulmonary circulation received the whole of cardiac output as ventricular outputs must be equal
◦ Despite equal volume, pulmonary circulation is a low pressure system
How is systemic pressure measured?
Plethysmography
Briefly explain measuring pulmonary pressure
• Pulmonary capillary pressure is measured by Capillary Wedge Pressure
◦ Slightly higher than left atrial pressure
◦ Used to estimate left atrial pressure
◦ Measured using Catheter put through right side into the branch of the pulmonary artery
◦ It wedges at the pulmonary capillaries and stops flow
How is vessel resistance affected by inhalation
• As lung expands during inspiration, the extra-alveolar vessels (vessels that run through the lung) are pulled open
◦ This distention means lung resistance is low at high volumes and equally resistance is higher at low volumes
◦ This is offset by the effect on capillaries
How are capillaries affected by inhalation
• Capillaries are squashed as lung volume rises meaning that capillary resistance rises as lung volume does and falls similarly
◦ Alveolar capillaries are so thin that they are distended by blood pressure yet compressed by air pressure
Explain pressure differences in the lung and it’s effect on flow
◦ Given the height of the lung and the low pressure circulation, there is a difference in pressure between the base and the apex which gives 3 zones of flow being:
‣ Zone 1: No flow and only occurs in certain circumstances where capillary systolic pressure less than alveolar: PA (Alveolar) > Pa (Arterial) > Pv (Venous)
‣ Zone 2: Intermittent flow where capillary diastolic pressure less than alveolar: Pa > PA > Pv
‣ Zone 3: Continuous flow where capillary diastolic pressure more than alveolar (most of lung): Pa > Pv > PA
‣ In exercise, there is an increase in pressure causing continuous flow in all of lung
Note that flow depends on aA gradient and not av gradient
What gradient is flow dependent on? (In the lung)
Arterial and alveolar
What has lower resistance, systemic or pulmonary circulation
Pulmonary
How does the pulmonary system adjust to increased volume demands?
• The pulmonary circulation can take larger cardiac output without increasing resistance or pressure
◦ Pulmonary blood volume is approximately 500 ml
◦ Volume can increase to some extent without a change in pressure or resistance through capillary recruitment and distension
What occurs to pulmonary blood in conditions of SNS?
• In conditions of SNS activation, up to 50% of pulmonary volume can move into systemic circulation (due to constriction)
Describe the Control of Pulmonary Resistance
Control of Pulmonary Resistance Through Hypoxic Pulmonary Vasoconstriction:
• The pulmonary system has relatively low extrinsic (neural/hormonal) influence
• It has no Myogenic or metabolic effects as in other beds other than the recruitment and distension
• Oxygen is a hugely important factor and pulmonary circulation behaves differently to systemic arteries
◦ Rather than dilation, Hypoxia leads to constriction in the pulmonary circulation (Hypoxic Pulmonary Vasoconstriction)
‣ Intrinsic mechanism
‣ This response controls capillary perfusion shunting blood away from poorly ventilated areas to match ventilation (V) and perfusion or flow (Q)
• This is an important mediator in Hypoxic Disease as high altitude may cause pulmonary vasoconstriction ultimately leading to Pulmonary Hypertension and Edema and even right heart failure
Describe the effect of sterling forces on Pulmonary Edema
• Similar to systemic circulation, pulmonary circulation is also affected by Sterling Forces
◦ Values in the lung are different due to the low pressure nature of the circulation
◦ Hydrostatic Pressures: Low pressure means capillary pressure is low and lymphatic pumping means interstitial pressure is lower which causes more fluid to move to interstitium (path of least resistance)
◦ Oncotic Pressure: Leaky capillaries allow more colloid in interstitium which causes more fluid to move to the interstitium
List the two mechanisms alveolar fluid is removed before being carried away by lymphatics
• Fluid in the Alveoli leave by one of two mechanisms before being carried away by lymphatics
◦ Active pumping of Na+ creating an osmotic gradient or the negative interstitial pressure sucks it out
What is the result of Pulmonary Edema
◦ Interstitial Edema increases the diffusion distance for O2 and decreases lung compliance.
‣ If it reaches positive interstitial fluid pressure, fluid crosses alveolar membranes giving alveolar edema
‣ Potentially fatal due to suffocation
What are the main causes of Pulmonary Edema
• Major causes of Pulmonary Edema:
◦ Rises in pulmonary capillary pressure
‣ Left heart failure leads to failure of the circulation and pulmonary congestion increases capillary pressure
‣ High altitude Hypoxic pulmonary vasoconstriction
‣ In chronic conditions, lymphatics can expand to compensate
◦ Increases in pulmonary capillary permeability
‣ Damage to capillary in conditions like Pneumonia (infection that inflames air sacs)
‣ Damage leads to leakiness and a decrease in the Oncotic (Colloid osmotic pressure) holding fluid in the capillary
