CVS 6 - Blood vessel order, functions & specialisation of cells in the CVS

Question 1

What is the vascular endothelium?

Answer 1

Single cell layer that acts as the blood-vessel interface.

Has multitude of important functions.

Question 2

What are the 5 key functions of the endothelium?

Answer 2

• 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

Question 3

How is endothelial function assessed?

Answer 3

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.

Question 4

What is arachidonic acid? Describe how it is produced.

Answer 4

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.

Question 5

How are Thromboxane A2 and prostacyclin (PGI2) synthesised from arachidonic acid?

Answer 5

Arachidonic acid ————-> Prostaglandin H2 (PGH2)
Enzyme: COX1 + COX2
Prostaglandin H2 can then be converted to:
Thromboxane A2 (by Thromboxane Synthase)
Prostacyclin (by Prostacyclin Synthase)

Question 6

What is the action of thromboxane A2 and prostacyclin?

Answer 6

Thromboxane A2: Vasoconstrictor (++)
Pro-platelet
Pro-atherogenic

Prostacyclin does the opposite even if they have the same precursor PGH2
Vasodilator (–)
Anti-platelet
Anti-atherogenic

Question 7

What are the two main vasodilatory molecules? What other effect do they have?

Answer 7

Nitric Oxide
Prostacyclin
Inhibit the aggregation of platelets

Question 8

What are the three main vasoconstricting molecules? Which of them has an effect on platelets?

Answer 8

Thromboxane A2 - activates platelets
Endothelin-1
Angiotensin II

Question 9

What is special about endothelin-1?

Answer 9

Endothelin-1 can cause BOTH vasoconstriction AND vasodilation - it has different receptors on different tissues
However more potent vasocontrictor

Question 10

Describe the synthesis of nitric oxide.

Answer 10

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)

Question 11

Describe the action of nitric oxide.

Answer 11

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

Question 12

What is the precursor and source of NO?

Answer 12

Precursor: L-Arginine

Diet

Question 13

What is the enzyme in NO synthesis?

Answer 13

eNOS

Question 14

What is the role of the endothelial cell in NO synthesis and action?

Answer 14

Source of eNOS

Question 15

What is the VSMC second messenger for NO?

Answer 15

GC

GC converts GTP to cGMP

Question 16

What is the NO receptor on the VSMC?

Answer 16

There is no receptor. NO diffuses directly into cell and activates GC.

Question 17

What role does acetylcholine play in blood vessels?

Answer 17

Acetylcholine UPREGULATES eNOS

This leads to steady vasodilation

Question 18

What enzyme produces arachidonic acid from DAG?

Answer 18

DAG lipase

Question 19

What is the precursor of prostacyclin? How is it obtained in the endothelial cell?

Answer 19

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.

Question 20

Describe the mechanism of action of prostacyclin.

Answer 20

Prostacyclin binds to IP1 receptor on VSMC and activates AC —> increase in cAMP —> activate PKA —> inhibits MLCK –> reduces cross bridges cycling –> relaxation

Question 21

What is the role of the endothelial cell in PGI2 synthesis?

Answer 21

Major source of PGH2 (from which PGI2 is synthesised with prostacyclin synthase)

Question 22

What is prostacyclin’s receptor?

Answer 22

IP1

Question 23

What is prostacyclin’s VSMC second messenger?

Answer 23

AC which converts ATP to cAMP

Question 24

Where is thromboxane produced?

Answer 24

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

Question 25

What are the two types of receptor for thromboxane and where are they found?

Answer 25

``` TPAlpha = Platelets TPBeta = Smooth Muscle Cell ```

Question 26

Describe the mechanism of action of thromboxane on vascular smooth muscle cells.

Answer 26

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

Question 27

What is the role of the endothelial cell in TXA2 synthesis?

Answer 27

Major source for PGH2

Question 28

What is TXA2's VSMC second messenger?

Answer 28

PLC which converts PIP2 to IP3

Question 29

How is endothelin-1 (ET-1) produced?

Answer 29

Endothelial cell nucleus produces zymogen Big Endothelin-1. This is converted to endothelin-1 by enzyme Endothelin Converting Enzyme (ECE).

Question 30

What two types of receptors does endothelin-1 have? Where are they situated?

Answer 30

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

Question 31

What is the mechanism of action of endothelin-1 on VSMC?

Answer 31

ET1 binds to ETA or ETB on VSMC | Receptor releases PLC which converts PIP2 to IP3 which triggers Ca2+ influx --> cell CONTRACTS

Question 32

What is the mechanism of action of endothelin-1 on endothelial cell and then VSMC?

Answer 32

ET1 binds to ETB on endothelial cell This upregulates eNOS so NO is produced. NO will diffuse into VSMC and induce cell relaxation.

Question 33

What is ET-1's precursor? What enzyme is used to convert it to ET1?

Answer 33

Big Endothelin-1 converted by ECE to ET1

Question 34

What is the role of the endothelial cell for ET1?

Answer 34

Precursor source and enzyme source

Question 35

What is ET-1's VSMC 2nd messenger system?

Answer 35

PLC which converts PIP2 to IP3

Question 36

Describe the production of angiotensin II.

Answer 36

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)

Question 37

What effects do angiotensin II have?

Answer 37

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

Question 38

What other action does ACE have other than converting angiotensin I to angiotensin II?

Answer 38

It breaks down bradykinin into bra + dyki + nin

Question 39

Describe angiotensin II's mechanism of action

Answer 39

Diffuses through endothelial cell. Binds to AT1 receptor on VSMC. PLC converts PIP2 to IP3 which will induce contraction.

Question 40

What is the mechanism of action of bradykinin on endothelial cells and what effect does it have?

Answer 40

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

Question 41

Describe the mechanism of action of aspirin

Answer 41

Apirin permanently disables COX enzymes and subsequent prostaglandin synthesis (platelets can't recover, endotherlial cells produce new enzymes) Aspirin is a NSAID

Question 42

Describe the mechanism of action of nitrovasodilators

Answer 42

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)

Question 43

Describe the mechanism of action of calcium channel blockers

Answer 43

Blocks the flow of channel into cells and so subsequently contraction and so decreases BP.

Question 44

What is the problem with designing calcium channel blockers and what is the solution?

Answer 44

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