Lecture 19 - Beta-2 Adrenoceptors Flashcards
Pathology of chronic obstructive pulmonary disease.
Multiple parallel, intersecting processes, rather than one linear pathology.
Factors involved in pathology of COPD
1)
2)
3)
1) Acute inflammation
2) Chronic inflammation
3) Airway remodelling
Leads to narrowing of airways
Drugs that remedy airway smooth muscle shortening (narrowing of lumen)
Relievers, controllers, preventers
Drugs that remedy bronchial wall oedema and mucus hyper secretion
Preventers
Example of preventer-class drugs
Glucocorticoids
How long after allergen introduction does it take for acute inflammation to begin?
Around half an hour
What do controller-class drugs act on?
Smooth muscle of the airways.
Decrease likelihood of smooth muscle spasm.
Reliever-class drugs
Used in response to acute need. Decreases tonicity of airway smooth muscle
Preventer-class drugs 1) 2) 3) 4)
Used to reduce the amount of allergen-stimulated inflammatory mediators
1) Acetylcholine
2) HA
3) LTC4 (Leukotrienes)
4) LTD4
Mediators involved in relaxation of respiratory smooth muscle
1) Adrenaline
2) Prostaglandin E2
3) PGI2
Exogenous mediator of relaxation of respiratory smooth muscle
Beta-2 adrenoceptor agonists
Healthy state of functional antagonism between mediators of contraction and relaxation of respiratory smooth muscle
Relaxants predominate
Contractile agonist active in the nM range
Histamine
What leads to contraction of respiratory smooth muscle?
Increase in intracellular [Ca2+]
Ways to increase intracellular calcium levels
1)
2)
3)
1) TRP channels
2) Voltage-operated calcium channels (from depolarisation)
3) Phospholipase C/inositol triphosphate-mediated Ca2+ release form intracellular stores
Ways to decrease intracellular calcium levels
1)
2)
1) Plasma Ca2+ ATPase extrudes Ca2+ from cell
2) Sarcoplasmic reticulum Ca2+ ATPase (SERCA) uptakes Ca2+ into intracellular stores
How can you measure intracellular Ca2+ in airway smooth muscle?
Stain with a dye that binds to Ca2+, changes colour when it does so. Expose airways to different stimuli, measure Ca2+ fluorescence
Example of a long-acting beta-agonist
Formoterol
How do ACh, HA, LTC4 and LTD4 affect intracellular Ca2+ levels?
1)
2)
3)
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.
How does PLC activation affect smooth muscle tone?
1)
2)
3)
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.
How do beta-2 adrenoceptor agonists relax smooth airway muscle? 1) 2) 3) 4) 5) 6)
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
Short-acting beta-2 adrenoceptor agonists
1)
2)
1) Salbutamol
2) Terbutaline
Key features of short-acting beta-2 adrenoceptor agonists
1)
2)
3)
1) Rapid onset (2-5 mins)
2) Beta-2 selective
3) Effective for 2-4 hours
Long acting beta-2 adrenoceptor agonists
1)
2)
1) Salmeterol
2) Formoterol
Salmeterol
1)
2)
3)
1) Long-acting beta-2 adrenoceptor agonist
2) Slow onset
3) 12 hour duration
Formoterol
1)
2)
3)
1) Long-acting beta-2 adrenoceptor agonist
2) Rapid onset
3) 12 hour duration
How are controllers (long-acting beta-2 adrenoceptor agonists) used?
1)
2)
3)
1) Used for prophylaxis
2) Combined with glucocorticoids in a single actuator
3) Reduces likelihood of symptoms. No substantial anti-inflammatory action.
SMART findings
Asthma deaths increased from 0.45 to 1.98 per 1000 per patient years with beta-2 agonist therapy
Non-selective beta agonist
Isoprenaline
Potential issues with beta-2 adrenoceptor agonist treatments
1)
2)
1) Could mask underlying inflammation in airways, without addressing cause of inflammation
2) Tolerance to drug could develop
Findings with beta-2 adrenoceptor -/- mouse studies
Absence of beta-2 adrenoceptors in the airways leads to less airway contraction upon contact with allergen.
Drug that protects against murine asthma
A beta-2 inverse agonist.
Nandolol.
Nandolol
A beta-2 inverse agonist
Why might the absence of beta-2 adrenoceptors lead to less severe asthma in mice?
A small proportion of empty beta-2 adrenoceptors might signal. Inverse agonists prevent this ‘empty signalling’ by stabilising inactive receptor.
Effects of nandolol on humans and mice
Reduces airway reactivity in asthma.
