Blood Flow Regulation Flashcards
What percentage of the blood sits in the veins at any one time
60% - veins are a reservoir
What vessels regulate blood pressure
Arterioles
Give 5 functions of the vascular endothelium
Barrier - diffusion and transport
Clotting system - von willebrand
Cell adhesion - macrophage entry
Structural components for basement membrane
Produces vasoactive substances
What are the 3 vasodilating substances produced by vascular endothelium
Nitric oxide
Prostacyclin
Endothelium-derived hyperpolarising factors EDHF
What are the 3 vasoconstricting substances produced by vascular endothelium
Endothelin I
Angiotensin II
Endothelium-derived contracting factor (s)
ACE - conversion to angiotensin II and degradation of bradykinin (vasodilator)
How is nitric oxide produced
Produced by L-arginine
What are the 3 types of NO
eNOS - Endothelial cells (continually expressed)
nNos - neural cells (continually expressed)
iNOS - inflammatory cells normally
How is iNOS beneficial in infection
Also an oxidising agent so can kill pathogens
Functions of eNOS
Controls regional blood flow and blood pressure (ALWAYS ON)
How does eNOS trigger smooth muscle relaxation
Shear stress is placed on the wall of the vessel due to the blood flow –> this causes calcium to move down the concentration gradient to inside the cell –> this binds to calmodulin –> calmodulin activates eNOS –> eNOS activates cGMP which decreases calcium and therefore causes smooth muscle relaxation
How long is eNOS halflife
5-10secs
How does prostaglandin I2trigger smooth muscle relaxation
Shear stress is placed on the wall of the vessel due to the blood flow –> this causes calcium to move down the concentration gradient to inside the cell –> this makes phospholipase A2 –> arachidonic acid –> COX –> PGI2 –> cCAMP which decreases calcium and raises intracellular potassium –> hyperpolarised (relaxation)
How does EDHF trigger smooth muscle relaxation
Shear stress is placed on the wall of the vessel due to the blood flow –> this causes calcium to move down the concentration gradient to inside the cell –> this makes phospholipase A2 –> arachidonic acid –> P450 Enzyme –> EET –> potassium hyperpolarisation –> stops voltage-gated Ca channels opening
Can also do it independently through potassium
Give three mediators that can bind to receptors sites to trigger vasodilation
ACh
Thrombin
Bradykinin
Why is NO always produced
To help keep resistance vessels open
What is the association between size of vessel and NO
The smaller the vessel the less effective NO is (EDHF is better)
What happens to EDHF and NO ratio with age
Declines
What happens when NO and PGI2 are both activated
Synergistic effect
How does cardiac output change during exercise
Increases 5 fold
How does the blood change between skeletal muscle
20% to 80% but brain remains unchanged
Define autoregulation
Maintenance of constant tissue blood flow when perfusion pressure changes
What is the myogenic response
Found in arterioles - with a rise in flow the lumen narrows (and vice versa)
What is the purpose of the myogenic response
To maintain autoregulation
End organs want a constant flow therefore the vessels will constrict to an increase in flow to keep the flow down at normal level and constant (and vice versa).
What causes the myogenic response
Mechanical, not neurological just vessel wall tension.
What happens to the membrane potential as transmural pressure increases
Becomes more positive - depolarises
What ion is required for the myogenic response
Extracellular calcium
In summary, how does the myogenic response work
Increase in transmural pressure –> depolarisation –> voltage senstive Ca2 channels open –> rise in Ca2 –> Rise in tension
What are the two hypotheses that link transmural pressure and membrane potential
1 - stretch-activated cation channels
2 - phospholipase A (PLA2) activation and HETE formation
How does the stretch activation cation channel hypothesis work
Patch-clamp of coronary artery smooth muscle cells revealed stretch sensitive non-selective Na channels
What goes against the stretch-activated cation channel hypothesis
The degree of stretch was non-physiological and Na has shown not to be important
What is the HETE scheme
Increase in tension –> increase in PLA2 –>Increase in arachidonic acid –> P450 –> HETE –> Closes K channels –> depolarisation –> opens voltage gated calcium channels–> vasoconstriction
Ca as negative feedback as a rise closes the K channels
How does the vasodilative factors of the endothelium and the vasoconstrictive factors of the myogenic response work together
Will always have flow even with a change of pressure -
With a rise of pressure and some level of flow, get an initial increase in diameter which then drops as a result of myogenic response but then the vessel diameter increases again - this is because the increase in pressure activates shear stress which in turn activates nitric oxide
How does NO inhibit the myogenic response
P450 is needed in HETE formation. P450 contains a haem group that is bound by NO and inhibited resulting in a decrease in HETE and therefore a decrease in the myogenic response
To what extent is the neural input involved in endothelium interaction
The sympathetic nervous system only affects blood vessels - vasoconstriction but with vasodilation, an increase in sheer stress is present - causing a rise in NO and therefore vasodilation so overall - vasoconstriction but not as severe as flow needs to be maintained
No parasympathetic control
When does the myogenic effect dominate in Skeletal muscles
At rest as low flow
What happens to skeletal muscle blood flow when it is used
Flow effect (Nitric oxide) overrides myogenic tone to allow greater tissue supply
What affects terminal arterioles to cause vasodilation
Low O2
High CO2
Low PH
High lactate
High potassium
High phosphate
High adenosine
High osmolarity
Basically, anything which suggests supply less than demand
How does hypoxia cause vasodilation in skeletal cells
Low ATP and high ADP so opens ATP sensitive K channels to hyperpolarise and relax smooth muscle.
Unlikely to last the whole time of muscle use but maybe first trigger for vasodilation
What does acidosis do to blood vessels and how
Dilates via K ATP channels - seen in the brain
What muscles are insensitive to blood PCO2
Heart and skeletal muscle
Can lactate cause vasodilation for skeletal muscels
No - mcardle syndrome produces no lactate as no glycogen phosphorylase to use glycogen for anaerobic glycolysis. These patients still get normal vasodilation
Can lactate cause vasodilation for skeletal muscles
Can do in isolated vessels via NA/K pump causing hyperpolarisation and therefore vasodilation HOWEVER - Topical application of K to skeletal muscles causes too slow of vasodilation to account for the rapid increase in blood flow seen in vivo.
Can ATP cause vasodilation for skeletal muscle
Inorganic phosphate - produced when muscles contract as use of ATP, but this doesn’t work for sustained muscle activity.
Pi infusion into skeletal muscles didn’t raise blood flow
Adenosine - Works well by acting on A2 receptors and released by active tissues but only raises it 20-40%
Can osmolarity cause vasodilation for skeletal muscle
No - hyperosmotic solution put into infused limb doesn’t cause a sufficient blood rise
Likely to be more important in GI tract and liver that deal with high osmolarity levels
What actually causes local metabolic vasodilation
Not yet discovered - although adenosine may be important
Likely to be multifactorial with synergistic effects.
What are the vasodilating effects of EET being used to investigate for
WIDER READING - BIHZAD
EET has a vasodilator effect in the perfused mesenteric bed, partly through activation of vanilloid receptor. A strategy to elevate the levels of EETs may have a significant impact in correcting microvascular abnormality associated with diabetes.
How can EET be used to prevent microvascular damage in diabetes
EXTRA READING
Can help cause vasodilation in diabetic patients - current research in analogues and soluble epoxide hydrolase inhibitors (enzyme that hydrolysis EET)
What changes occur in vascular substrates when exercise is induced long-term
Raised NO
Lower endotheliun
What cells are required for myogenic response
Just smooth muscle cells
What cells are required for flow mediated vasodilation
Both - endothelial cells and smooth muscle cells.
Do all vasodilative factors get activated at the same time
No depends on the abundance of each part of the pathway in each cell
Do all vasodilative factors get activated at the same time
No depends on the abundance of each part of the pathway in each cell
What did laughlin and muller discover relating to the myogenic response in 1988
That it was due to a stretch effect - This increase in basal myogenic tone in arterioles from exercise-trained
swine appears to be specific to stretch-mediated contractions. Thus neither the receptor-mediated vasoconstriction by acetylcholine and endothelin, nor the vasoconstriction in response to direct voltage-gated calcium channel activation by K and the L-type calcium channel
agonist BAY K 8644 were altered by exercise training
How can myogenic tone affect coronary hypoperfusion
Bache and Dunker 1994
Autoregulation is a local effect and becomes clinically important when stenosis occurs - In this situation, high proximal resistance decreases the distal perfusion pressure therefore myogenic tone comes in to raise this pressure within the coronary artery.
How can alpha 2 receptors appose vasoconstriction
Cocks and angus 1983
Alpha 2 receptors release nitric oxide to maintain coronary flow through vasodialtion
What did the study by gladwin et al 2004 suggest about the role of blood in combating the myogenic tone
When myogenic tone was done in vitro in isolation, the nitric oxide response was triggered and sustained much longer than in vivo. This is believed to be because the absence of RBCs in the lumen of isolated arterioles limits the degree of NO scavenging by haemoglobin causing a build-up of NO
What is the myogenic tones role in reactive hyperaemia
Eikens and wilcken 1973
Myogenic dilation may contribute to a small component of the initial phase of reactive hyperemia. Reactive hyperemia is the increase in blood flow that results after the release of a transient occlusion (lasting typically for 10–
120 seconds). Historically, reactive hyperemia has been attributed to the buildup of metabolites during the period
of occlusion [1], but the fall in arterial pressure downstream from the
occlusion could potentially provide a stimulus for myogenic dilation. As it is so quick its unlikely to be metabolic
What is the link between myogenic tone and adrenergic response
Lui and Hill 1994
Myogenic tone can cause vessel constriction reducing the diameter to 50%
However, 50% is not the absolute limit of constriction because subsequent application of adrenergic agonists, at
an appropriate concentration, will cause additional constriction [72,109], and in some cases, near-complete vessel
closure
How is the formation of 20-HETE stimulated
EXTRA READING - Miyata
in vascular smooth muscle is stimulated by
angiotensin II, endothelin and norepinephrine
How is 20-HETE inhibited?
EXTRA READING - Miyata
Nitric oxide
What role does HETE play in strokes
Kehl et al 2002
20-HETE rises in haemorrhagic strokes to raise cerebral BP in autoregulation. This does however increase the risk of vasospasm at a later date.
High levels of 20-HETE have been found in CSF post SAH
What is TS-011 and its role with 20-HETE in strokes
Miyata et al 2005
Its an inhibitor of 20-HETE and has shown to decrease infarction size post-stroke
Hoped that this can be converted into medication in the future to decrease post-stroke mortality.
