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Vasodilation Lecture notes
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Detailed, neat and organised lecture notes on vasodilation and vasoconstriction. includes diagrams
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VASODILATIONLEARNING OUTCOMES
TO UNDERSDTAND INFLUENCE OF NITRIC OXIDE ON VASCULAR FUNCTION
TO UNDERDSTAND MECHANISMS LEADING TO VASODILATION
NITIRIC OXIDE
- Vasodilator capacity- important aspect that relates to control of blood vessel function and to the
control of blood perfusion into tissues through the diameter regulation of vessels.
Back in 1982, scientists, Furchgott and Zawadazki, 1980 did some work and discovered the role of the
endothelial derived reactant factor (EDRF)
o In the aortic vessel this important factor is nitric oxide
1. The experimental work they did was to isolate the
rabbits aorta, clear it from surrounding fat, and then cut
it into rings.
2. Then they adapted the organ bath so that they were
able to mount the rings between two fine steel wires
3. The fine steel wires are inserted through the lumen of
this aortic vessel
4. The bottom wire is attached to a wire and the upper
wire is attached to a signal transducer
o It’s possible to move away these wires from
each other because this bottom bit is actually
connected to a micrometre
5. As you move these wires away, you stretch the vessel
6. You are mimicking take place in vivo (inside and animal)
when the vessel is under pressure.
o All our blood vessels are under pressure
7. You can actually stretch this even further to generate elevated pressure
8. You can control the amount of stretch and consequently modelling depression
9. This vessel is them put inside a chamber and this is them immersed in physiological salt solution-
saline solution that is closest to the solution in the body
10. This is maintained, it is gassed, and it is also maintained at a temperature of 35-36 degrees
o and so therefore this is an ex vivo model which mimics what takes place inside the animal
o Can then monitor the change in tension as a function of time
Example output we would get->
Top image: change in tension as a function of time
- Trace of the tension- the scientists maintained the vessel and then
added noradrenaline. This led to a sudden increase in tension. This is
because the vessel constricted. They then added accumulative
concentration of an agonist acetylcholine and influenced the function
of the vessel wall and they found that there was a reduction in
diameter- depicting relaxation of the vessel
, Bottom image:
Repeated the above process by rubbing the vessel.
- So they got the aortic vessel and rubbed it. They then mounted the second vessel, and they
repeated the process. They added noradrenaline and got constriction- more than they did the first
time. When they added these cumulative concentrations of acetylcholine, they found that there
was no overall change in tension. When they washed, they found that this was the only way to
relax the vessel and get it to return to normal.
- Found that acetylcholine was causing relaxation only in the vessels that had an intact inner layer of
endothelial cells. Because when you do the rubbing, you’re actually damaging the endothelial cells.
They discovered that acetylcholine is acting on the endothelial cells to induce the release of a
vasodilator. They called this endothelial derived relaxant factor. Also found that the dilator is nitric
oxide and that if you inhibit nitric oxide production, you see something similar to the bottom
image.
Nitric oxide:
It’s a diffusible gas that is produced widely in the body
A neurotransmitter in the central and peripheral nervous system
Labile, short half-life ~ 10-60 sec
Important role in vascular homeostasis
- Imbalance of NO production is implicated in various clinical conditions
- Overexpression of NO can be detrimental to function
- E.g. Impaired NO production is associated with hypertension, atherogenesis
In terms of homeostasis
Actions of NO:
- Immune function, normally:
o Inhibit platelet adhesion and aggregation
o Inhibit monocyte adhesion and migration
o Inhibit SMC and fibroblast proliferation (Host defence: Contributes to cytotoxic killing
mechanisms of immune cells)
NO is a Reactive oxygen species and therefore at very high levels it has an important host defence
mechanism and will contribute to cytotoxic killing.
- Vascular function
o Induces SMC relaxation via activation of cGMP dependent protein kinases in smc.
Synthesis and breakdown of NO:
- Synthesised by the oxidation of amino acid (part of diet) L-Arginine -> L-citrulline + NO (bi product)
o Cofactors: NADPH, BH4, oxygen, Calmodulin
- NO is short acting- very quickly oxidised to nitrites and nitrates
Oxygenated haemoglobin
Molecular Oxygen
Superoxide anions
- Forms nitrosothiols in the tissues– release NO over a longer time period
- L-arginine is usually presented in excess in the endothelial cell cytoplasm and so the rate of nitric
oxide production is determined by the activity of the enzymes
o Enzymes like nitric oxide synthases are key to this process.
Synthesis and breakdown of NO:
- Nitric oxide synthases: 3 isoforms
o eNOS- endothelial- constitutively expressed
found in the association of caveola. And so the dissociation will activate the enzyme.
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