8 - Vascular endothelium 1 Flashcards
What is the vascular endothelium?
A single layer of cells that act as the blood-vessel interface.
What are the functions of the vascular endothelium?
Vascular tone - secretes and metabolises vasoactive substances.
Thrombostasis - prevents clot formation/molecules adhering to vessel wall
Absorption and secretion - Allows active and passive transport via diffusion/channels.
Barrier - Prevents atheroma development and stops pathogens.
Growth - Mediates cell proliferation
What does exogenous mean?
Something that comes from outside the body - not made yourself. E.g. a hormone which is given to a patient.
What is Laser Doppler flowmetry?
Used to assess vascular function.
Acetylcholine is given to intact endothelium (response)
Acetyl choline is given to no endothelium (no response)
Nitric oxide is given exogenously (response)
What is flow mediated dilation?
Blood vessel is fluorescently marked. Change in diameter measured with stimulus. - blood pressure cuff.
Not used in clinical practise due to high change of errors.
What is arachidonic acid?
The starting point to make Thromboxane A2 and Prostacyclin.
What is arachidonic acid made from?
Made from phospholipids in cell membrane.
Phospholipase A2.
What thing changes arachidonic acid into PGH2? What is the next step of synthesis?
COX1 and COX2.
Then either…
Thromboxane synthase makes Thromboxane A2
Prostacyclin synthase makes prostacyclin
What are the properties of thromboxane A2?
Vasoconstrictor
Pro-atherogenic
Pro-platelet
What are the properties of prostacyclin?
Vasodilator
Anti-atherogenic
Anti-platelet
What is PGH2 also associated with that causes specific symptomss?
PGD2, PGE2, PGF2.
Pain, inflammation, fever.
What is the method of action of Nitric Oxide?
- ACH binds to GPCR
- Phospholipase C converts PIP2 to IP3.
- IP3 triggers Calcium release from ER
- Calcium release triggers eNOS enzyme
- eNOS turns L-arginine (precursor) to NO
- NO diffuses into vascular smooth muscle cell
- NO activates GC (Guanylyl cyclase)
- GC converts GTP to cGMP.
- cGMP upregulates PKG which activates potassium channels.
- Membrane hyperpolarises.
- Cell relaxes
- Vessel dilates
What is the method of action of prostacyclin?
- PGH2 is the precursor.
- PGI2 enzyme is made via COX.
- PGI2 binds to IP receptor.
- Upregulation of adenylyl cyclase.
- ATP converted to cAMP
- cAMP inhibits MLCK
- Reduced cross bridge cycling
- Cell relaxes
- Vessel dilates.
What is the method of action of Thromboxane A2? Both in VSMC and blood.
In VSMC:
- TXA2 diffuses through apical and basement membrane and binds to TP1 receptor.
- PLC converts PIP2 to IP3.
- Triggers calcium influx from extracellular space and SER.
- Calcium upregulates MLCK
- Contraction
- Vessel constricts
In blood:
- TXA2 binds to receptors on platelet
- Platelets become active and produce more TXA2.
- Positive feedback
- Platelets aggregate
How is angiotensin II synthesised?
Angiotensinogen is made in the liver.
Renin is made in the kidneys.
Renin causes angiotensinogen to become angiotensin I.
ACE makes angiotensin I become angiotensin II.
How does angiotensin II cause increased water retention?
It causes…
ADH secretion
Aldosterone secretion
Tubular sodium reabsorption
How does angiotensin II cause increased vascular resistance?
Arteriolar vasoconstriction
Sympathoexcitation
What is the overall combined effect of angiotensin II?
Increased blood pressure
What is the method of action of angiotensin II?
- Ang II diffuses across endothelium
- Binds to AT1 receptor
- PLC converts PIP2 to IP3
- IP3 triggers calcium influx.
- Calcium upregulates MLCK
- Contraction & vasoconstrition
(small action as a vasodilator as NO is made too)
ALSO
ACE metabolises bradykinin.
NO mediated vasodilation is reduced.
What is the method of action of endothelin I?
- Endothelial cell nucleus produces big endothelin 1
- ECE converts this to ET1
- ET1 binds to receptors on VSMC
- PLC released, PIP2 to IP3, Calcium influx
- Cell contracts, vasoconstriction
ALSO
ET1 binds to ET8 on endothelial cell
Upregulated eNOS
increased NO production = small effects as vasodilator.
What drugs can be used to treat hypertension?
ACE inhibitors.
Angiotensin receptor blockers
How does aspirin work?
Inactivates COX1 by aspirin acetylation
Aspirin acetylation switches function of COX2 to generate protective lipids.
Lowers levels of thromboxane (produced in platelets where there is no nucleus that can produce more)
Is the inactivation of COX by aspirin reversible?
No, its irreversible
Other NSAIDs cause reversible inactivation of COX
How do calcium channel blockers work?
Prevent calcium entering VSMC
