The Circulation Flashcards
CIrculation; Flow; Vascular starling forces; Lymphatic system; Law of LaPlace; Vascular endothelium; Vascular endothelium drugs
What are the two main physical principles of the circulatory system?
Double circulation - systemic and pulmonary, each with different pump
Pressure gradient - generated by heart, causes movement of blood
What is the function of the circulatory system?
Transport oxygen, CO2, nutrients, hormones, metabolites, cells and immunity related molecules around the body
Thermoregulation
What is the general order of the circulatory vessels?
Arteries -have a low sfa -store little blood but at high fluctating pressure Arterioles -site of drop in BP -can be constricted to control flow of blood Capillaries -highest total sfa -form networks/beds for diffusion Venules -connect veins to capillary beds Veins -holds the most blood and at the lowest pressure
Define laminar flow
Velocity of fluid constant at any one point
Flows in layers
Fastest closest to centre of lumen (some friction with endothelial cell lining)
High level of shear stress - promotes endothelial cell survival and alignment in direction of flow to promote secretions to allow vasodilation and anticoagulation
Define turbulent flow
Associated with pathophysiological changes to endothelial lining
Erratic flow
Forms eddys
Prone to pooling
may lead to occlusion
Low shear stress promotes endothelial proliferation allows secretions to promote endothelial proliferation, apoptosis and shape change
What does the parabolic velocity profile show?
Shows how flow further from the wall = increased velocity
Tangent at any point on the parabolic profile = shear rate
shear rate x velocity = shear stress
What is shear stress?
Governs how well endothelial cells work
shear rate x viscosity
How is turbulent flow used in the measurement of blood pressure?
Release of BP cuff leads to turbulent flow
Can be heard with stethoscope
What is Poiseuille’s equation and its importance?
resistance = (8×length×viscosity)/(π×r^4)
length and viscosity are effectively constant so only radius changes rapidly
halving radius decreases flow 16 fold ∴ capillaries and arterioles have the most resistance to flow
What is vascular compliance?
The relationship between transmural pressure and vessel volume
change in volume/change in pressure
Dependent on vessel elasticity
Venous>arterial
Define elastance
Inverse of compliance
ΔPressure/Δvolume
Produced by elastin fibres in the vascular wall which leads to recoil upon stretching
Blood vessels with high compliance will have low elastance
arterial>venous
∴arteries recoil to maintain pressure whilst veins distend
What is the Windkessel effect?
Dampening effect of the change in pressure during ejection
Blood enters aorta faster than it is leaving ∴ 40% of stroke volume is stored by elastic arteries
when ejection ends and aortic valve closes, elastic arteries recoil and send off all stored blood
∴aortic pressure falls slowly and blood isnt lost all at once
How can compliance be modulated?
Externally - by stockings to reduce pooling in veins
Internally - by the Renin-angiotensin-aldosterone system, endogenous vasodilators/constrictors and vasoactive drugs
What is the effect of gravity on flow?
pulls blood towards ground
standing causes increased hydrostatic pressure ∴blood trasiently pools in veins due to high compliance
∴reduced venous return ∴ reduced CO and BP (starlings law)
Why do healthy individuals not faint when they stand up?
Standing activates SNS
constrict venous smooth muscle to stiffen veins
constrict arteries to increase resistance and maintain BP
increase HR and force of contraction to maintain CO
What is the relationship between the Law of LaPlace and blood flow?
increased radius increases flow but also leads to higher wall stress ∴ thicker wall is needed to produce higher tension as the radius increases for a given pressure
What is an aneurysm?
Balloon like distension increases radius of vessel
For same pressure, tension increases
If weakened fibres cannot supply needed force then will distend in negative feedback cycle until RUPTURE
What is the microcirculation?
Specific to each organ
1st order arterioles
Covered in smooth muscle
Branch to capillaries via terminal arterioles to enter tissues
Pre-capillary sphincters control blood flow to capillary bed
Venules leave tissue to collect blood and deliver to the heart
What is a fluid circuit?
Flow rate=pressure gradient/resistance
mainly affected by vessel radius - poiseuilles eqn
Where is the pressure gradient formed within the microcirculation?
Between arteriole and capillary
What would decrease the Windkessel effect?
decrease in arterial compliance
Where is the pressure gradient for a fluid circuit found?
between arteriole and capillary
Why do the radii of arterioles vary?
Local intrinsic control - matching blood flow to specific tissue needs
Extrinsic control - regulating BP
What is the formula for organ flow?
ΔP(MAP)/Resistance of organ
What is active hyperemia?
Increase in organ blood flow associated with increased metabolic activity of an organ or tissue
e.g. when activity of muscle increases, metabolism within that muscle increases ∴ so does oxygen consumpton, local tissues detect these increases and send a signal to the arterioles, arterioles vasodilate and increase oxygen reaching cells
What is myogenic vasoconstriction?
Local tissue responds to changes in physical environment like temperature changes ∴ if things get colder, this is sensed and sends signals that cause arterioles to vasoconstrict and reduce heat loss
Also respond to changes in pressure e.g. if big increase in BP to organ that doesn’t require extra flow, arterioles vasoconstrict to help direct greater blood flow to other organs
What is the general structure of a capillary?
Single endothelial cell wall
Diameter big enough form 1 cell
Extensive branching
minimises diffusion distance, maximises diffusion time and maximises sfa
What are the 3 types of capillary?
Continuous
Fenestrated
Discontinuous
What are features of a continuous capillary?
junctions between endothelial cells are filled with water
∴allows water soluble and small molecules to diffuse over gap junctions
Found in blood-brain barrier but these have no H2O gap junctions and only lipophilic molecules can leave and enter
What are features of a fenestrated capillary?
Circular fenestrae
Slightly more leaky ∴allows larger molecules to leave blood
Found in glomerulus kidney nephron
What are features of a discontinuous capillary?
Very large gap junctions
Allows large molecules to leave blood
Found in bone marrow
What is bulk flow?
Volume of protein free plasma that filters out of the capillary, mixes with surrounding interstitial fluild and is reabsorbed
What affects bulk flow?
2 Starling forces
Hydrostatic pressure - from the heart, pushes fluid out
Oncotic pressure - pulls fluid back into capillaries
What is ultrafiltration?
when pressure inside capillary>pressure in the interstitial fluid
What is reabsorption?
When inwards driving pressure>outwards driving pressure
Why is the lymphatic system needed?
Hydrostatic pressure at arteriolar end>venular end but oncotic pressure same throughout ∴net loss
∴lymphatic system needed
What is the structure of the lymphatic system?
Blind ended capillaries with a single layer of endothelial cells lie alongside blood capillaries
Have a large water filled channel that reabsorbs excess interstitial fluid
Has valves to ensure one way flow that depends on skeletal contraction/respiratory pumps
Lymph nodes that have immune detection defence mechanisms
Drainage into R lymphatic duct + thoracic duct then R and L subclavian veins for recirculation
What causes elephantitis?
Parasitic blockage of lymph nodes preventing fluid recirculation
What causes oedema?
Production rate of ISF>removal rate
What is the structure of the vascular endothelium and the functions of each layer?
Layer of cells that acts as a blood-vessel interface
Lumen - hollow, where blood flows
3 layers:
tunica intima - one cell thick, allows for exchange and haemostasis
Internal elastic tissue
tunica media - unconsciously controlled smooth muscle
External elastic tissue
tunica adventitia/externa - protects vessel and contains nerves and blood supply to vessel
What are the main functions of the vascular endothelium?
Vascular tone management
-secrete and metabolise vasoactive substances
Barrier
-prevents atheroma development and impedes pathogens
Growth
- mediates cell proliferation
Thrombostasis and haemostasis
-prevents clots forming or molecules adhering to vessel wall
Absorption and secretion
-allows active/passive transport via diffusion/channels
What are prostaglandins?
group of compounds that can affect vascular tone
How are prostaglandins synthesised?
1) Phospholipids converted to arachidonic acid by phospholipase A₂
2) Arachidonic acid converted to prostaglandin H₂ by COX1/2
3) converted to prostacyclin by prostacyclin synthase OR converted to thromboxane A₂ by thromboxane synthase OR converted to inflammatory mediators
What is thromboxane A₂?
Prostaglandin that is a :
Vasoconstrictor
Pro-atherogenic
Pro-platelet
What is prostacyclin?
Prostaglandin that is a :
Vasodilator
Anti-atherogenic
Anti-platelet
What are key vasodilators?
Endothelium derived: Nitric oxide Prostacyclin Non-endothelium derived: Kinins ANP
What are key vasoconstrictors?
Endothelium derived: Thromboxane A₂ Endothelin-1 Non endothelium derived: Angiotensin II ADH Noradrenaline adrenaline
What are the sources of nitric oxide?
Exogenous - diffuses from blood to vascular smooth muscle cells
Endogenous - produced in response to Ach/bradykinin binding and shear stress
How is nitric oxide synthesised in the body?
1) ACh binds to G protein coupled receptor
2) Activates phospholipase C and moves along membrane
3) Phospholipase C catalyses PIP₂ -> IP₃
4) this triggers Ca2+ release from ER
5) this upregulates endothelial nitric oxide synthase
6) eNOS converest L-arginine and oxygen to L citrulline and nitric oxide
How does nitric oxide cause vasodilation?
NO diffuses into vascular smooth muscle cells
Activates guanylate cyclase to convert GTP to cGMP
cGMP upregulates protein kinase G
Protein kinase G activates K+ channels
Causes hyperpolarisation and cell relaxation
How does prostacyclin cause vasodilation?
Prostacyclin diffuses into vascular smooth muscle cells
Binds to membrane IP receptors
This activates adenyl cyclase to convert ATP to cAMP
cAMP inhibits myosin light chain kinases causing cell relaxation and vasodilation
How does Thromboxane A₂ cause vasoconstriction?
Binds to TPbeta receptors on VSMCs
Activates phospholipase C to migrate along membrane and convert PIP₂ -> IP₃ and DAG
IP₃ triggers Ca2+ influx from ER
Ca2+ upregulates myosin light chain kinase causing VSMC contraction and vasoconstriction
ALSO
Binds to TPalpha receptors on platelets = activation
Produce more Thromboxane A₂ in positive feedback response
Platelets aggregate for haemostasis
How does endothelin-1 cause simultaneous vasoconstriction and vasodilation?
Endothelial cell produces big endothelin 1
Endothelin converting enzyme converts zymogen to ET-1
ET-1 binds to ETa and ETb receptors on VSMC
Receptors release PLC
PLC converts PIP₂ to IP₃
IP₃ triggers Ca2+ influx
Cell contracts and vessel constricts
ET-1 also binds to ETb on endothelial cell
Upregulates eNOS
Increased NO production
NO diffuses into VSMC
Cell relaxes
Vessel dilates
How does angiotensin II cause vasoconstriction?
Renin cleaves angiotensinogen to Ang I
ACE expressed on endothelial cells in renal/pulmonary circulation and cleaves Ang I to AngII
Ang II diffuses across endothelium and binds to AT1 receptor
Causes Phospholipase C to migrate along membrane and convert PIP₂ to IP₃
IP₃ triggers Ca2+ influx
Ca2+ upregulates myosin light chain kinase
Cell contracts
ACE also metabolises bradykinin reducing NO mediated vasodilation
Vessel constricts
What is the mechanism of action of ACE inhibitors?
Block ACE molecules from converting Ang I to Ang II
This means Ang II doesnt bind to AT1 receptor and contraction does not take place
Bradykinin is also not metabolised
Instead bradykinin binds to B1 receptor and stimulates production of NO
Causing vasodilation
What is the mechanism of action of aspirin?
Aspirin is an irreversible inhibitor of the COX enzyme
(NSAIDS are reversible inhibitors)
Inactivates COX-1
Switches function of COX-2 to generate protective lipids
∴SHOULD decrease thromboxane levels but also prostacyclin
BUT in low doses prostacyclin falls slightly but is still quite high and thromboxane levels continue to fall
This because thromboxane mainly made by platelets that have no nuclei to replace COX enzymes
Prostacyclin made by endothelial cells and these are able to produce more COX enzymes and overcome the effects of aspirin
This means aspirin has anti-platelet effects
What does the endothelium produce?
Adhesion molecules Matrix products Antithrombotic/procoagulant factors Vasodilating/vasoconstricting factors Growth factors
What is the difference between resting endothelium and activated endothelium?
Resting: -anti inflammatory -anti thrombotic -anti proliferative Activated: -Pro inflammatory -Pro thrombotic -pro angiogenic
What are activating factors that have an effect on the endothelium?
Viruses Smoking Mechanical stress Inflammation High blood pressure OxLDL High glucose
What are the main processes of endothelium activation?
Thrombosis
Senescence
Increased permeability
Leukocyte recruitment
What is senescence?
Damaged/ageing cells undergo growth arrest to halt proliferation in response to stress/damage
Stops damaged cells replicating but cells become pro-inflammatory and contribute to CVD
Why is increased permeability of activated endothelium bad?
Increased permeability allows plasma protein leakage and for lipoproteins to pass over and bind to proteoglycans where they are oxidised before macrophages engulf them to form foam cells
These foam cells contain cholesterol and can lead to plaque formation = atherosclerosis
How is leukocyte recruitment altered when the endothelium is activated?
Normally they recruit and adhere to the endothelium of post-capillary venules and then migrate into tissues and use enzymes to leave vessels
When endothelium activated leukocytes recruit and adhere to the endothelium of large arteries, migrate into the sub-endothelial space and then get stuck because arteries thick
therefore leukocytes accumulate in large arteries
What is the mechanism of action of Ca2+ channel blockers?
Prevents IP₃ causing a Ca2+ influx to VSMCs
∴prevents contraction and vasoconstriction
What is the mechanism of action of nitrovasodilators?
Found in GTN sprays
Contains NO functional group which donates ready to use NO
This is short acting and drops BP in the short term
What is autoregulation and its main theories?
Intrinsic capacity to compensate for changes in perfusion pressure by changing vascular resistance
Myogenic theory
Metabolic theory
Injury
What is the myogenic theory of autoregulation?
Smooth muscle fibres respond to tension in vessel wall
∴increased pressure = contraction and reduced perfusion causes relaxation
What is the metabolic theory of autoregulation?
As blood flow decreases, metabolites accumulate
∴causing dilation to increase flow and wash metabolites away
What is the injury related theory of autoregulation?
Serotonin release from platelets causes constriction