CVS 6 - Blood vessel order, functions & specialisation of cells in the CVS Flashcards
What is the vascular endothelium?
Single cell layer that acts as the blood-vessel interface.
Has multitude of important functions.
What are the 5 key functions of the endothelium?
- Vascular tone -> secretes and metabolises vasoactive substances (constriction/dilation)
- Thrombostasis -> prevents clots forming or molecules adhering to vessel wall
- Absorption & secretion -> Allows active/passive transport via diffusion/channels
- Barrier -> prevent atheroma development and impedes pathogens
- Growth -> mediates cell proliferation
How is endothelial function assessed?
By Laser Doppler flowmetry
Can compare change in blood flow with different administrations (like ACh) and also when endothelium is damaged/healthy to see difference.
What is arachidonic acid? Describe how it is produced.
Formed from phospholipids out of lipid bilayer with enzyme Phospholipase A2.
It is a precursor for a lot of things such as
Prostacyclin, Thromboxane A2 and prostaglandins typically involved in pain, fever, inflammation.
How are Thromboxane A2 and prostacyclin (PGI2) synthesised from arachidonic acid?
Arachidonic acid ————-> Prostaglandin H2 (PGH2)
Enzyme: COX1 + COX2
Prostaglandin H2 can then be converted to:
Thromboxane A2 (by Thromboxane Synthase)
Prostacyclin (by Prostacyclin Synthase)
What is the action of thromboxane A2 and prostacyclin?
Thromboxane A2: Vasoconstrictor (++)
Pro-platelet
Pro-atherogenic
Prostacyclin does the opposite even if they have the same precursor PGH2
Vasodilator (–)
Anti-platelet
Anti-atherogenic
What are the two main vasodilatory molecules? What other effect do they have?
Nitric Oxide
Prostacyclin
Inhibit the aggregation of platelets
What are the three main vasoconstricting molecules? Which of them has an effect on platelets?
Thromboxane A2 - activates platelets
Endothelin-1
Angiotensin II
What is special about endothelin-1?
Endothelin-1 can cause BOTH vasoconstriction AND vasodilation - it has different receptors on different tissues
However more potent vasocontrictor
Describe the synthesis of nitric oxide.
A substrate, ACh, that triggers NO production will bind to a Gq protein linked receptor and activate PLC. This migrates along membrane and sees PIP2:
PIP2 —-> IP3 + DAG
IP3 —-> triggers [Ca2+] release from SR
Increased [Ca2+] —> activates endothelial nitric oxide synthase (eNOS)
eNOS converts:
L-arginine + Oxygen —> L-citrulline + NO
(NO then diffuses into VSCM)
Describe the action of nitric oxide.
Nitric Oxide diffuses into cell and activates GUANYLYL CYCLASE (GC)—> transforms GTP to cGMP (this will be part of the cell secondary messenger system)—> activation of Protein Kinase G —> causes K influx –> RELAXATION
What is the precursor and source of NO?
Precursor: L-Arginine
Diet
What is the enzyme in NO synthesis?
eNOS
What is the role of the endothelial cell in NO synthesis and action?
Source of eNOS
What is the VSMC second messenger for NO?
GC
GC converts GTP to cGMP
What is the NO receptor on the VSMC?
There is no receptor. NO diffuses directly into cell and activates GC.
What role does acetylcholine play in blood vessels?
Acetylcholine UPREGULATES eNOS
This leads to steady vasodilation
What enzyme produces arachidonic acid from DAG?
DAG lipase
What is the precursor of prostacyclin? How is it obtained in the endothelial cell?
Arachidonic acid.
Can be produced from DAG with DAG lipase (this is produced like for NO; bindin of ACh to endothelial cell activates PLC then PIP2 which is converted to DAG or IP3) or from phospholipid by phospholipase A2.
Describe the mechanism of action of prostacyclin.
Prostacyclin binds to IP1 receptor on VSMC and activates AC —> increase in cAMP —> activate PKA —> inhibits MLCK –> reduces cross bridges cycling –> relaxation
What is the role of the endothelial cell in PGI2 synthesis?
Major source of PGH2 (from which PGI2 is synthesised with prostacyclin synthase)
What is prostacyclin’s receptor?
IP1
What is prostacyclin’s VSMC second messenger?
AC which converts ATP to cAMP
Where is thromboxane produced?
Endothelial Cells - same pathway as for production of prostacyclin
Platelets - TXA2 binds to TPalpha receptor on platelet -> activates platelet -> makes them sticky + produce more TXA2
What are the two types of receptor for thromboxane and where are they found?
TPAlpha = Platelets TPBeta = Smooth Muscle Cell
Describe the mechanism of action of thromboxane on vascular smooth muscle cells.
Thromboxane diffuses through apical and basement membranes of endothelial cell then binds to TPBeta receptor on VSMC and activates PLC which finds PIP2
PIP2 —> IP3 + DAG
IP3 induces calcium release from SER
Increase in Ca2+ which activates MLCK –> VASONCONSTRICTION
What is the role of the endothelial cell in TXA2 synthesis?
Major source for PGH2
What is TXA2’s VSMC second messenger?
PLC which converts PIP2 to IP3
How is endothelin-1 (ET-1) produced?
Endothelial cell nucleus produces zymogen Big Endothelin-1. This is converted to endothelin-1 by enzyme Endothelin Converting Enzyme (ECE).
What two types of receptors does endothelin-1 have? Where are they situated?
ETA - on the VSMC
ETB - on the endothelial cell and VSMC
Endothelin-1 diffuses out of endothelial cell after its production and then can bind same cell or go on VSMC
What is the mechanism of action of endothelin-1 on VSMC?
ET1 binds to ETA or ETB on VSMC
Receptor releases PLC which converts PIP2 to IP3 which triggers Ca2+ influx –> cell CONTRACTS
What is the mechanism of action of endothelin-1 on endothelial cell and then VSMC?
ET1 binds to ETB on endothelial cell
This upregulates eNOS so NO is produced.
NO will diffuse into VSMC and induce cell relaxation.
What is ET-1’s precursor? What enzyme is used to convert it to ET1?
Big Endothelin-1 converted by ECE to ET1
What is the role of the endothelial cell for ET1?
Precursor source and enzyme source
What is ET-1’s VSMC 2nd messenger system?
PLC which converts PIP2 to IP3
Describe the production of angiotensin II.
Renin is released by juxtaglomerular cells
Renin converts angiotensinogen (produced by the liver) to angiotensin I
Angiotensin I is converted to Angiotensin II by ACE (mostly found in the lung endothelium)
What effects do angiotensin II have?
Increase Vascular Resistance:
Vasoconstriction
Increase sympathetic activity
Increase Water Retention:
Increase sodium reabsorption
Increase vasopressin (aka ADH) secretion
Increase aldosterone production
–> this all contributes to increase BP
What other action does ACE have other than converting angiotensin I to angiotensin II?
It breaks down bradykinin into bra + dyki + nin
Describe angiotensin II’s mechanism of action
Diffuses through endothelial cell. Binds to AT1 receptor on VSMC.
PLC converts PIP2 to IP3 which will induce contraction.
What is the mechanism of action of bradykinin on endothelial cells and what effect does it have?
Bradykinin binds to its receptor on endothelial cells (B1) when ACE is not breaking it down.
PLC: PIP2 —-> IP3 + DAG
Results in UPREGULATIONG OF eNOS —–> increase in NO —–> VASODILATION
This is the opposite effect of ANG-II
Describe the mechanism of action of aspirin
Apirin permanently disables COX enzymes and subsequent prostaglandin synthesis (platelets can’t recover, endotherlial cells produce new enzymes)
Aspirin is a NSAID
Describe the mechanism of action of nitrovasodilators
Medication that includes a NO functional group
Donates ‘redy-to-use’ NO
This will difuse into VSMC and have effect
Used to treat angina (too short action to use for HT)
Describe the mechanism of action of calcium channel blockers
Blocks the flow of channel into cells and so subsequently contraction and so decreases BP.
What is the problem with designing calcium channel blockers and what is the solution?
A calcium channel blocker needs to be designed such that it doesn’t interfere with the calcium channels in the heart.
Solution: the affinity of the calcium blocker to the channel is dependent on MEMBRANE POTENTIAL
Smooth muscle cells have a MORE POSITIVE membrane potential than cardiomyocytes
