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BMS 242 - CVS respiratory > Respiration III > Flashcards

Respiration III Flashcards

1
Q

What controls the diameter of the lumen of the airways?

What is this dependant on?

A

Airway smooth muscle

Dependant on GPCR cascades that make the muscle contract/relax

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2
Q

How is the overall relaxation/contraction state of the airway smooth muscle determined?

A

By the OVERALL activation fo the 3 GPCR cascades:

  • Gq
  • Gs
  • Gi
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3
Q

What are the receptors of the Gq pathway?

A
  • M3 muscarinic
  • H1 histamine
  • BK bradykinin
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4
Q

What is the Gq pathway linked to?

A

Airway CONSTRICTION

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5
Q

What is the Gq pathway that stimulates airway CONTRACTION?

A

1) Agonist binds to the receptor and activates G protein Gq
2) Gq stimulates PHOSPHOLIPASE C
3) PIP2 splits into DAG and IP3
4) IP3 activates the cascade - releases calcium from stores
5) Changes to the membrane potential - open Ca2+ voltage gated channels
6) Influx of calcium across the cell membrane
7) Smooth muscle contraction

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6
Q

What are the receptors that activate the Gs pathway?

A
  • Beta2 adrenergic receptors

- VIP receptors

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7
Q

What is stimulation of the Gs pathway linked to?

A

Airway RELAXATION

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8
Q

What is the Gs pathway that stimulates airway RELAXATION?

A

1) Activate G2 subunit
2) Stimulate ADENYLATE CYCLASE
3) Production of cAMP
4) Stimulation of protein kinase A
5) PKA leads to phosphorylation
6) Leading to smooth muscle relaxation

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9
Q

As well as activating adenylate cyclase, what else does Gs do?

What does this lead to?

A

Activate the BK K+ channel:

1) K+ out of the cell - hyperpolarisaion (more negative inside)
2) INACTIVATES Ca2+ channels
3) Membrane is FURTHER AWAY for VG Ca2+ channels to open - preventing muscle contraction

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10
Q

What are the receptors acting through the Gi pathway?

A

M2 muscarinic receptors

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11
Q

What does the Gi pathway lead to?

What does this cause?

A

INHIBITION of ADENYLATE CYCLASE

  • Counteracts the stimulatory effect of Gs activation (normally relaxes the airways)
  • OPPOSES smooth muscle relaxation
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12
Q

As well as inhibiting adenylate cyclase, what else does Gi do?

What does this lead to?

A

INHIBITS the the BK K+ channel

1) K+ DOESN’T move out of the cell
2) Membrane potential is MORE positive - MORE chance of Ca2+ channels being open

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13
Q

What are the 3 controls of of the airway smooth muscle?

A

1) Sympathetic nervous system
2) Parasympathetic nervous system
3) Humoral factors

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14
Q

How does the sympathetic nervous system control the smooth muscle of the airways?

A

Release of NOREPINEPHRINE

Leads to DILATION

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15
Q

How does the parasympathetic nervous system control the smooth muscle of the airways?

A

Release of acetylcholine from the VAGUS NERVE

Leads to CONSTRICTION

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16
Q

What receptors does Ach from the vagus nerve act on?

A

Muscarinic receptors

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17
Q

What HUMORAL factors control the smooth muscle of the nervous system?

A

1) Epinephrine - leads to DILATION

2) Histamine - leads to CONSTRICTION

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18
Q

When is histamine released?

A

During inflammatory responses

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19
Q

How does histamine lead to constriction?

A
  • Activation of the H1 receptor

- Activates the Gq pathway

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20
Q

Where are the receptors involved in parasympathetic control present?

Which receptors control smooth muscle contraction?

A

1) Postganglion neurons
- M2 receptors

2) Airway smooth muscle (target)
- M2 and M3 receptors

M3 receptors control smooth muscle contraction

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21
Q

What is the negative feedback in the control of smooth muscle contraction in parasympathetic control?

A

1) Ach released from postganglionic nerve
2) SOME Ach travels across the cleft and activates M3 receptors
3) SOME Ach feedback on the M2 receptors on the postganglionic nerve - preventing further release of Ach

22
Q

What happens if the feedback mechanism in the parasympathetic control of smooth muscle is disrupted?

A

Leads to ASTHMA and HYPERSENSITIVE airways

23
Q

What happens when the M3 receptors are activated through parasympathetic control?

A

Contraction of the brachial smooth muscle:
1) Ach bind to M3 receptors - activating the Gq pathway

2) Increase in intracellular Ca2+ (through activation of phospholipase C, IP3 formation from PIP2 etc.)
3) Ca2+ bind to CaM to form Ca2+/calmodulin
4) Ca2+/calmodulin binds to myosin light chain kinase (MLCK) - allowing another kinase to phosphorylate MLCK to activate it
5) MLCK phosphoylates the myosin light chain
6) Cross-bridge formation formed by the myosin
7) Contraction of the smooth muscle

24
Q

What happens at the same time as the Gq pathway in smooth muscle contraction in the airways?

A

Protein kinase C (PKC) phosphylates and INHIBITS myosin light chain PHOSPHATASE

–> PREVENTING relaxation of the muscle

25
Q

How is contraction of the airway smooth muscle stopped?

A

By allowing activation of MLCP - can remove the phosphate from the myosin chain and prevent cross-bridge formation

26
Q

What is a beta2 adrenoreceptor agonist?

What happens when it binds to B2 adrenoreceptors?

A

Salbutamol

When bind:

  • Activate the receptor
  • Activate the Gs pathway
  • Activating PKA (through activation of adenylate cyclase and cAMP)
27
Q

What does PKA phosphorylate to induce smooth muscle relaxation?

What does this cause?

A

Phosphorylates MLCK at a DIFFERENT SITE to PKC

Causes a REDUCTION in the activity of MLCK

28
Q

What does the reduction of Ca2+ inside the cell (through the activation of BK K+ channels in muscle relaxation) cause?

A
  • Turns off Ca2+/CaM signalling

- Inactivates MLCK

29
Q

At the same time as the activation of B2 adrenoreceptors by the SNS to increase muscle relaxation, what also occurs?

What does this cause

A

1) Activation of BK K+ channels

2) Stimulation of MLCP
- Dephosphorylation of myosin light chain
- Loss of cross linking

30
Q

What is asthma caused by?

A

Hypersensitive airways

Due to the increase in parasympathetic activity and M2 receptors

31
Q

What are the 2 triggers for asthma?

A

1) Atopic (extrinsic)

2) Non-atopic (intrinsic)

32
Q

What are the atopic triggers of asthma?

A

Allergens/allergies

33
Q

What are the non-atopic triggers of asthma?

A
  • Respiratory infections
  • Stress
  • Cold air
  • Exercise
  • Inhaled irritants
34
Q

What is the response in asthma?

A

1) Movement of inflammatory cells into the airways
2) Release of inflammatory mediators
3) BronchoCONSTRICTION

35
Q

What are the inflammatory mediators released from inflammatory cells during asthma?

A

Histamine

36
Q

Describe the spirometry in asthma

A
  • VC (vital capacity) in NORMAL range
  • FEV1 (forced expiratory volume in one second) is <80% of FVC (forced vital capacity)
  • Reduction in FEV1%

(Final volume is the SAME, but takes LONGER to expel the air)

37
Q

How are hypersensitive airways caused?

A
  • Inhibition of the negative feedback of Ach on the M2 receptors
  • More Ach released
  • Hypersensitivity
38
Q

What does hypersensitivity affect the muscles of the airways?

A

Increases BASAL TONE

Increases MUSCLE CONSTRICTION in response to irritants

39
Q

In the antigen-challenge, what is the change in M2 function linked to?

How?

A

Eosinophils:

  • Cluster around the nerve fibres
  • Activated eosinophils release major basic protein (MBP)
  • MBP acts as an AGONIST and inhibit the M2 receptors
  • INHIBITS negative feedback
  • Overproduction of Ach and airway oversensitivity
  • Over contraction
40
Q

What does ozone exposure cause?

A

Activation of the eosinophil pathway:

  • Synthesis of MBP
  • Inhibition of receptors
41
Q

What does virus exposure cause the activation of?

A
  • Macrophages
  • Neuraminidase
  • Interferons
42
Q

What does the activation of neuraminidase cause?

A

Cleavage of part of the M2 receptor and changes to the binding affinity for Ach

43
Q

What does the activation of interferons cause?

A

Reduced M2 gene expression

44
Q

How are cases of asthma REDUCED in diabetics?

A

Insulin reduces M2 receptors

Reduced insulin in diabetics

45
Q

What are 3 treatments for asthma?

A

1) Beta2 adrenergic agonists
2) Anticholinergics
3) Glucocorticoids

46
Q

What do Beta2 adrenal agonists do?

A

Acitvate the Gs pathway

47
Q

What are the shorter acting Beta2 adrenal agonists?

A

Salbutamol

48
Q

What are the longer acting Beta2 adrenal agonists?

What must this be delivered with?

A

Salmeterol

Delivered with corticosteroids

49
Q

What do anticholinergics do?

A
  • BLOCK the effects of Ach on the M3 receptor
  • Preventing activation of the Gq pathway
  • Causing airway relaxation
50
Q

What do glucocorticoids do?

A

Anti-inflammatory:
- Prevent the binding of eosinophils to the nerve terminals

  • Upregulate anti-inflammatory genes
  • Inhibit inflammatory genes

BMS 242 - CVS respiratory (15 decks)

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