Lecture 14

Question 1

What happens when the endothelium is removed?

Answer 1

Acetylcholine results in contraction

Question 2

What happens when endothelium is present?

Answer 2

Acetylcholine results in relaxation

Question 3

What was discovered when the epithelium was present?

Answer 3

EDRF - endothelium derived relaxing factor

Question 4

What was the EDRF identified as?

Answer 4

The gas nitric oxide

Question 5

Why did Robert Furchgott, Louis Ignarro and Ferid Murad win the normal prize in 1998?

Answer 5

For their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system

Question 6

What does NO generate?

Answer 6

Smooth muscle relaxation via stimulation of cGMP production

Question 7

How is NO broken down?

Answer 7

It is rapidly broken down by free radicals (O2-) and by haemoglobin

Question 8

What is the NO signalling pathway synthesised from?

Answer 8

L-arginine by eNOS (endothelial nitric oxide synthase)

Question 9

What does NO toncially control?

Answer 9

Vascular resistance

Question 10

How can you inhibit eNOS?

Answer 10

With L-NMMA which Inhibits blood flow by 50%

Question 11

What is the inhibition of eNOS reversed by?

Answer 11

L-arginine

Question 12

How often is NO released?

Answer 12

It is released continuously to control blood flow

Question 13

What is the most important control of NO release?

Answer 13

SHEAR STRESS is the signal, not flow

Question 14

What does an increase in NO synthesis increase?

Answer 14

It is increases with blood viscosity at a constant flow rate

Question 15

What does the degradation of glycocalyx =

Answer 15

Reduction in flow-induced NO production

Question 16

What is the stress signal transduced by?

Answer 16

Endothelial glycocalyx (integrins)

Question 17

What do integrins activate?

Answer 17

Phosphatidyl inositol 3 kinase

Question 18

What is the mechanisms for shear stress-induced NO production?

Answer 18

Stress signal is induced by endothelial glycocalyx,
Which actuates phosphatidyl inositol 3 kinase
Which phosphorylates protein kinase B
Which phosphorylates eNOS
And increase eNOS activity

Question 19

What does NO couples flow in?

Answer 19

Arterioles and conduit arteries

Question 20

What is metabolic hyperaemia?

Answer 20

Local control of blood flow

Question 21

What is the pathway for NO flow in arterioles and conduit arteries?

Answer 21

Vasodilation of arterioles,
Increase flow rate in upstream conduit artery,
Increase shear stress
Increase NO release

Question 22

What is another mechanism of endothelium-dependent relaxation?

Answer 22

Acetylcholine causes arterial relaxation and hyperpolarisation of smooth muscle cells

Question 23

What is another way for endothelium-dependent relaxation?

Answer 23

Inhibition of eNOS and PGI2 production which blocks later relaxation phase

Question 24

What is the early phase of hyperpolarisation and relaxation mediated by?

Answer 24

Endothelium dependent hyperpolarising factor (EDHF)

Question 25

What causes hyperpolarisation of the endothelial cell?

Answer 25

An agonist

Question 26

How can hyperpolarisation spread through the cell?

Answer 26

Via gap junctions

Question 27

What are candidate EDHFs?

Answer 27

K+, EET, hydrogen peroxide, c-natriuretic peptide

Question 28

What are the agonists that cause hyperpolarisation through the cell?

Answer 28

Thrombin, bradykinin, acetylcholine

Question 29

What are some examples of endothelium derived vasoactive substances?

Answer 29

Nitric oxide, EDHF, prostacyclin (PGI2), endothelin

Question 30

What does the EDHF factor do?

Answer 30

Causes vasodilation in small vessels, especially arterioles

Question 31

What is prostacyclin derived from?

Answer 31

Arachidonic acid

Question 32

What does prostacyclin do?

Answer 32

Vasodilation and prevents platelet adhesion to endothelial cells

Question 33

Describe endothelin?

Answer 33

It’s a peptide, contributes to vasoconstriction and has a small contribution to basal vascular tone

Question 34

Do NO, EDHF and PGI2 vary?

Answer 34

They vary between arterioles of different diameters and from different vascular beds

Question 35

Where is NO found in disease?

Answer 35

In essential hypertension, secondary hypertension, diabetes 1,2 and atheroma and dyslipidemia

Question 36

What is the role of NO in essential hypertension?

Answer 36

Abnormal production of NO implicated

Question 37

What is secondary hypertension?

Answer 37

Increased release of asymmetric dimethylarginine from damaged kidney

Question 38

What is the role of NO in diabetes 1 and 2?

Answer 38

Associated with a decreased NO production and decreased NO induced relaxation. Evidence of decreases insulin-mediated NO production

Question 39

What is the role of NO in septic shock?

Answer 39

Increase stimulation of iNOS production in macrophages and endothelial cells = massive vasodilation and increase in capillary permeability

Question 40

What does iNSO mean?

Answer 40

Inducible NOS

Question 41

What does septic shock result in?

Answer 41

Fall in blood pressure often fatal

Question 42

What could reverse hypotension?

Answer 42

L-NMMA treatment

Question 43

Describe the mechanism involved in NO formation and vasodilation?

Answer 43

Increases in ca2+ in endothelial cells induced by stimuli such as shear stress, blood flow and binding of agonists leads to formation of a ca2+ calmodulin complex which activates NO

Question 44

What is eNOS response for?

Answer 44

Most of the vascular NO production

Question 45

What happens to eNOS in a pathological state?

Answer 45

Becomes a potential ROS (reactive oxygen species) generator due to various oxidative stress

Question 46

What are the 3 different signalling pathways that regulate vascular tone?

Answer 46

Ca2+ signalling pathway, NO-cGMP, vascular signalling pathway

Question 47

What is vascular remodelling?

Answer 47

Alteration in radius of blood vessel and alteration in wall thickness of blood vessel

Question 48

What does outward remodelling result in?

Answer 48

Increased diameter

Question 49

What does inward remodelling result in?

Answer 49

Decreased diameter

Question 50

When does remodelling take place?

Answer 50

Physiological conditions, high altitude, endurance training and pathophysiological conditions

Question 51

Examples of physiological conditions?

Answer 51

Ageing, pregnancy

Question 52

High altitude examples?

Answer 52

Acute hypoxia, cerebral and pulmonary oedema, prolonged hypoxia

Question 53

What does endurance training change?

Answer 53

Conduit vessels have larger diameter, increase in number/density of arterioles (remodelling of capillaries driven by increase shear stress), capillary angiogenesis (VEGF) and increased mitochondria in muscle cells

Question 54

What VEGF?

Answer 54

Vascular endothelial growth factor

Question 55

Why could there be remodelling of vascular smooth muscle cells?

Answer 55

Responses to prolonged stimulation or pathophysiological insults

Question 56

What is the shift from a contractile to synthetic phenotype in smooth muscle cells associated with?

Answer 56

Reduction in myosin expression and molecular and functional alterations in ca2+ signalling

Question 57

What are examples of molecular and functional alterations in ca2+ signalling?

Answer 57

A move from L type to T type channel ca2+ entry, increasing involvement of TRP proteins in ca2+ cycling and switch in caMK11 isoforms

Question 58

What happens to vascular smooth muscle in response to injury?

Answer 58

It undergoes a phenotypic switch, a process that contributes to pathophysiological vascular wall remodelling