Basics of blood flow regulation Flashcards
Haemodynamic principle 1 - Darcy’s Law of Flow
- What is blood flow? What does Darcy’s law of flow suggest?
- How does Darcy’s law of flow relate to mean arterial pressure?
- Volume of blood that transmits through the capillary bed of a tissue in a given amount of time
>Flow is proportional to blood pressure gradient, and inversely proportional to blood flow resistance - MAP = CO x TPR
Haemodynamic principle 1 - Darcy’s Law of Flow
- What type of pump does the heart function as?
- What is the key role of the heart?
- How is arterial blood pressure regulated? Therefore how can we easily alternate blood flow to organs?
- Intermittent pump
- Creates large pressure gradient from aorta to vena cava and throughout CVS > essential to ensure blood flow
- Baroreflex > alteration in the resistance to blood flow
Haemodynamic principle 2 - Poiseuille’s Law
- What is the equation for resistance?
- What can small changes in the radius of blood vessels have significant effects on?
1.
2. Resistance of blood vessels
1.How can we combine Darcy’s and Poiseuilles law?
2. What is resistance proportional to?
3.What is resistance inversely proportional to?
- Fluid viscosity - Vessel length
- Vessel radius
- Vessels can be joined in series and parallel. Compare the resistance in both.
>Relate to blood flow in capillaries
In series R = sum of resistance of each vessel
e.g. R1+ R2 …..
In parallel e.g. CAPILLARY BED
R= the total conductance = the sum of the conductance (1/R) e.g. 1/Rtotal = 1/R1 + 1/R2 …..
>Sum of large number of conductance in parallel contributes to low resistance of capillary bed
»> Low velocity of blood flow enhances nutrient exchange
Why are arterioles known as resistance vessels?
Through arterioles, there is a main drop in pressure
→ ability to increase vascular resistance
→ We need a greater pressure gradient to drive blood through which indicates that arterioles is the area that opposes resistance to blood flow
- VSMC are abundant where? Contraction and relaxation of these cells causes what?
- Vasoconstriction / vasodilatation of pre-capillary arterioles can alter hydrostatic pressure in….
- Tunica media of resistance vessels NONE in capillaries
>vasocontraction and vasodilatation respectively thus altering the blood flow - Capillaries
What are the features of Vascular smooth muscles?
What control are they under?
- Non-striated
- Spindle shaped in appearance
- Consist of multi-units of smooth muscle cells
- Have a wide range of cell surface receptors to respond to variety of vasoactive compounds
- Have a broad array of ion channels on membrane, which are present in different quantities in different types of vessels
> Autonomic sympathetic control so they contract involuntarily
VSMC have cell surface receptors , what do they respond to?
-range of vasoactive compounds which means that they are able to modify their state of either contraction or relaxation based on information from the environment
VSMC have broad array of ion channels on membrane, why are they necessary?
- Necessary in some vessels for electro-mechanical contraction via increased intracellular [Ca2+]
> For some vessels, some VSMCs require membrane depolarisation for contraction, whereas others do not
……..The type of process of which these vessels contract is: Through a pharmaco-mechanical process
VSMC have a long cross-bridge duration, what does this ensure?
Ensures tension is maintained for a long time at little energy cost. (bind to target longer - some never relax )
Describe the process of vascular smooth muscle contraction.
- Increase in sarcoplasmic [Ca2+]
- Ca2+ binds and activates calmodulin
- Activated calmodulin binds and activates myosin light chain kinase (MLCK)
- Activated MLCK phosphorylates myosin heads and therefore myosin strands
- Phosphorylated myosin chain binds to actin chain which leads to cross bridge cycling, and then VSMC contraction
What does VSMC contraction depend on?
- Amount of Ca2+ in cytosol
- Sensitivity to Ca2+ (which is dictated by the balance between MLCK and myosin light chain phosphatase (MLCP) activity)
How does INTRACELLULAR Ca2+ rise in sarcoplasm (LARGE ARTERIES)
- e.g. Noradrenaline binds to alpha 1 adrenoreceptors which is GqPCR linked
- Catalysed activation of PLC
- PLC degrades membrane phospholipid PIP2 into IP3
- IP3 is soluble and diffuses into the cytosol and binds to specific receptors on SR → IP3 sensitive Ca2+ release channel > Channel opens so Ca2+ moves from SR into cytosol
- DAG is also a product from PIP2 which is insoluble so remains within the membrane, and diffuses by free movement in the membrane and binds to and activates receptor operated cation channel, allowing the entry of cations → mainly calcium
Why does most of the sarcoplasmic Ca2+ In large arteries come from the SR?
Hence what kind of process is this?
-In large arteries:
- VSMCs have well developed SRs = Big stores a lot of Ca2+
- VSMCs have few L-type VG Ca2+ channels as VSMC depolarisation and Ca2+ entry through these channels are not needed
> Pharmaco-mechanical process
How does INTRACELLULAR Ca2+ rise in arterioles?
- Noradrenaline binds to alpha 1 ARs which are GqPCRs
- This causes activation of PLC
- PLC acts on membrane phospholipids PIP2 to produce DAG and IP3
- DAG binds to receptor operated cation channel allowing some entry of calcium
- IP3 is going to diffuse inside the cytosol and bind to IP3 sensitive calcium release channel on the SR which releases a little bit of calcium
- Both of these mechanism allow for a small increase in intracellular calcium, which allows for activation of calcium activated chloride channel
- This will cause some level of depolarisation of the membrane as Cl- leaves the VSMCs as the inside becomes more positive
- Membrane depolarisation activates some L-type VG calcium channels, increasing their opening probability and increase the amount of calcium that enters the cell, which can cause an AP or not
- All of these mechanism together increase amount of intracellular calcium which then leads to contraction
Why does most of Ca2+ in arterioles come extracellularly?
Hence what kind of process is this?
- VSMCs have a small SR
- VSMCs have a high number of L-type VG Ca2+ channels - entry of Ca2+ via VG Ca2+ channels is required for contraction
Membrane dépolarisation may lead to Ca2+ based AP firing is this required for contraction?
-NO
- What is basal vascular tone?
- How do we know that there is a basal level of vasoconstriction?
- The base level of vasoconstriction that occurs within the body as a result of the range of vasoactive compounds that act on the VSMCs
- An arteriole in situ (within the body) will have a smaller lumen than ex situ (for example, in a Petri dish)
Which factors contribute towards the balance between vasodilatation and vasoconstriction?
Hence at rest, where does the balance favour?
We use an Integration of intrinsic and extrinsic factors to shape coordinated, whole body responses:
- What EXTRINSIC factors work on VSMC?
> What does it mean to be extrinsic? - What INTRINSIC factors work on VSMC?
>What does it mean to be intrinsic?
- Regulation of blood flow to an organ by factors originating outside the organ
- Regulation of blood flow to an organ by factors originating from within the organ
How is perfusion maintained when ΔP changes? MYOGENIC RESPONSE (Q=ΔP/R)
Answer questions using graph..
1. What does this graph show?
2.What happens when perfusion pressure is much smaller than MAP?
3.What happens when perfusion pressure is above MAP?
- As perfusion pressure increases, skeletal muscle blood flow increases
- After 30sec, blood flow becomes stable and is nearly constant
2.
3.
Answer the following questions based on this graph:
1. What does this graph show?
2.What happens when we add a Ca2+ channel blocker?
- Radius of arteriole increases as arterial pressure/perfusion pressure increases, hence increasing blood flow
> Increased radius means that stretch activated ion channels are activated, inducing a myogenic response, causing contraction
> Contraction causes vasoconstriction so arteriole radius immediately drops after this increase, which causes a further decrease in blood flow - There is no immediate decrease in arteriole radius, which tells us that the mechanism depends on entry of Ca2+ through Ca2+ channel through change of activity of stretch activated ion channels
> Ca2+ blocker → no contraction → no vasoconstriction→ no decrease in arteriole radius
How is vasodilatation caused in response to shear stress?
- The glycocalyx transduces information on shear stress
- Activation of intracellular protein kinase B (PKB)
- PKB phosphorylates endothelial nitric oxide synthase (eNOS) > ↑eNOS activity
- ↑ NO production in endothelial cells and diffusion through cell membranes to act locally in VSMCs
- NO activates guanylate cyclase in VSMCs > ↑cGMP production > Protein kinase G (PKG) activation which leads to:
> Inhibition of MLCK > ↓ Ca2+ sensitivity.
>↑ Ca2+ sequestration in SR via phosphorylation of phospholamban (which acts as a brake on SERCA, granting greater ability of SERCA to take calcium from cytoplasm and pump it back into SR)
How is 02 supply matched to metabolic demand
1.What does the cardiac output received by each organ generally depend on?
>What is the exception to this?
1.Metabolic rate
>Kidneys have higher blood flow than metabolic needs → consume 6% O2 but obtain 20% cardiac output at rest
» Excretion of waste products + maintenance of fluid homeostasis
» Organs have less blood flow for their metabolic needs > - How do they compensate for this?
- Can extract more oxygen from blood (such as the heart)
- Which vasoactive metabolites are excreted in the ECF from cells with increased metabolic rate? >Do they work alone?
- Discuss tissue specificity regarding response to metabolites.
- No single metabolite can fully explain metabolic hyperaemia
- Specific responses e.g. cerebral arterioles are especially sensitive to arterial pCO2
What is the Hierarchy of vascular tone control?
What does adrenaline cause in skeletal muscles?
-vasodilatation in skeletal muscle arterioles due to the abundance of β2 adrenoreceptor (Gs) compared to α1 adrenoreceptors (Gq) on VSMCs there.
How does signalling via b2 adrenoreceptor cause relaxation?
- Adrenaline binds to beta 2 AR which is GsPCR, in which Gs protein receptor activates AC
- increase in cAMP concentration, which then activates PKA, which then phosphorylates Phospholamban (PLN), which inhibits its braking action on SERCA, increasing the rate of sequestration of Ca2+ in SR
- PKA also phosphorylates potassium channel, increasing their open probability, allowing efflux of potassium
- This leads to hyperpolarisation of the membrane which further decreases the opening probability of VG calcium channels, so even fewer calcium ions can enter the cell
- PKA also phosphorylated MLCK, inhibiting its activity, preventing phosphorylation of myosin heads, and cross bridge cycling
> Decreased cytosolic [Ca2+] and decreased Ca2+ sensitivity → relaxation
- What is a Vasovagal syncope?
- What is a vasovagal faint ?
- A CNS reflex that triggers large changes in blood flow
- Perceived emotional stress becomes too great > vasovagal faint
>Similar to play dead response in animals
Veins can be divided into 4 functional compartments, what are these?
