Lecture 19 - Beta-2 Adrenoceptors

Question 1

Pathology of chronic obstructive pulmonary disease.

Answer 1

Multiple parallel, intersecting processes, rather than one linear pathology.

Question 2

Factors involved in pathology of COPD
1)
2)
3)

Answer 2

1) Acute inflammation
2) Chronic inflammation
3) Airway remodelling
Leads to narrowing of airways

Question 3

Drugs that remedy airway smooth muscle shortening (narrowing of lumen)

Answer 3

Relievers, controllers, preventers

Question 4

Drugs that remedy bronchial wall oedema and mucus hyper secretion

Answer 4

Preventers

Question 5

Example of preventer-class drugs

Answer 5

Glucocorticoids

Question 6

How long after allergen introduction does it take for acute inflammation to begin?

Answer 6

Around half an hour

Question 7

What do controller-class drugs act on?

Answer 7

Smooth muscle of the airways.

Decrease likelihood of smooth muscle spasm.

Question 8

Reliever-class drugs

Answer 8

Used in response to acute need. Decreases tonicity of airway smooth muscle

Question 9

Preventer-class drugs
1)
2)
3)
4)

Answer 9

Used to reduce the amount of allergen-stimulated inflammatory mediators

1) Acetylcholine
2) HA
3) LTC4 (Leukotrienes)
4) LTD4

Question 10

Mediators involved in relaxation of respiratory smooth muscle

Answer 10

1) Adrenaline
2) Prostaglandin E2
3) PGI2

Question 11

Exogenous mediator of relaxation of respiratory smooth muscle

Answer 11

Beta-2 adrenoceptor agonists

Question 12

Healthy state of functional antagonism between mediators of contraction and relaxation of respiratory smooth muscle

Answer 12

Relaxants predominate

Question 13

Contractile agonist active in the nM range

Answer 13

Histamine

Question 14

What leads to contraction of respiratory smooth muscle?

Answer 14

Increase in intracellular [Ca2+]

Question 15

Ways to increase intracellular calcium levels
1)
2)
3)

Answer 15

1) TRP channels
2) Voltage-operated calcium channels (from depolarisation)
3) Phospholipase C/inositol triphosphate-mediated Ca2+ release form intracellular stores

Question 16

Ways to decrease intracellular calcium levels
1)
2)

Answer 16

1) Plasma Ca2+ ATPase extrudes Ca2+ from cell

2) Sarcoplasmic reticulum Ca2+ ATPase (SERCA) uptakes Ca2+ into intracellular stores

Question 17

How can you measure intracellular Ca2+ in airway smooth muscle?

Answer 17

Stain with a dye that binds to Ca2+, changes colour when it does so. Expose airways to different stimuli, measure Ca2+ fluorescence

Question 18

Example of a long-acting beta-agonist

Answer 18

Formoterol

Question 19

How do ACh, HA, LTC4 and LTD4 affect intracellular Ca2+ levels?
1)
2)
3)

Answer 19

1) Bind to a GPCR coupled to Gq protein.
2) Gq protein activates phospholipase C
3) PLC cleaves PIP2 to IP3, which opens an IP3-gated Ca2+ channel in the cytoplasm.

Question 20

How does PLC activation affect smooth muscle tone?

1)
2)
3)

Answer 20

1) PLC cleaves PIP2 to IP3, which opens an IP3-gated Ca2+ ion channel in the cytoplasm.
2) Ca2+ activates myosin light-chain kinase, which activates actin/myosin ATPase activity.
3) PLC activates Rho kinase, which inhibits myosin light-chain phosphatase activity.

Question 21

How do beta-2 adrenoceptor agonists relax smooth airway muscle?
1)
2)
3)
4)
5)
6)

Answer 21

1) Bind beta-2 adrenoceptor (GPCR)
2) Gs protein attached to GPCR.
3) Gs activates adenylate cyclase, which increases cAMP levels
4) cAMP activates protein kinase A, which opens sarcoplasmic reticulum Ca2+ ATPase (SERCA), which takes Ca2+ into intracellular stores.
5) PKA inhibits IP3R ion channel
6) PKA inhibits myosin light-chain kinase, activates myosin light-chain phosphatase

Question 22

Short-acting beta-2 adrenoceptor agonists
1)
2)

Answer 22

1) Salbutamol

2) Terbutaline

Question 23

Key features of short-acting beta-2 adrenoceptor agonists
1)
2)
3)

Answer 23

1) Rapid onset (2-5 mins)
2) Beta-2 selective
3) Effective for 2-4 hours

Question 24

Long acting beta-2 adrenoceptor agonists
1)
2)

Answer 24

1) Salmeterol

2) Formoterol

Question 25

Salmeterol
1)
2)
3)

Answer 25

1) Long-acting beta-2 adrenoceptor agonist
2) Slow onset
3) 12 hour duration

Question 26

Formoterol
1)
2)
3)

Answer 26

1) Long-acting beta-2 adrenoceptor agonist

2) Rapid onset
3) 12 hour duration

Question 27

How are controllers (long-acting beta-2 adrenoceptor agonists) used?
1)
2)
3)

Answer 27

1) Used for prophylaxis
2) Combined with glucocorticoids in a single actuator
3) Reduces likelihood of symptoms. No substantial anti-inflammatory action.



Question 28

SMART findings

Answer 28

Asthma deaths increased from 0.45 to 1.98 per 1000 per patient years with beta-2 agonist therapy

Question 29

Non-selective beta agonist

Answer 29

Isoprenaline

Question 30

Potential issues with beta-2 adrenoceptor agonist treatments
1)
2)

Answer 30

1) Could mask underlying inflammation in airways, without addressing cause of inflammation
2) Tolerance to drug could develop

Question 31

Findings with beta-2 adrenoceptor -/- mouse studies

Answer 31

Absence of beta-2 adrenoceptors in the airways leads to less airway contraction upon contact with allergen.

Question 32

Drug that protects against murine asthma

Answer 32

A beta-2 inverse agonist.

Nandolol.

Question 33

Nandolol

Answer 33

A beta-2 inverse agonist

Question 34

Why might the absence of beta-2 adrenoceptors lead to less severe asthma in mice?


Answer 34

A small proportion of empty beta-2 adrenoceptors might signal. Inverse agonists prevent this ‘empty signalling’ by stabilising inactive receptor.

Question 35

Effects of nandolol on humans and mice

Answer 35

Reduces airway reactivity in asthma.