33 - Local Mediators and Pharmacological Modulation

Question 1

Exosomes

Answer 1

Membrane-bound sacs released by cells to communicate. Can have surface proteins, some sort of signalling molecules within exosome

Question 2

Why do local mediators often only act locally?
1)
2)

Answer 2

1) Often labile or rapidly degraded

2) Diluted too much beyond their point of release

Question 3

Three important examples of local mediators

Answer 3

1) Histamine
2) Bradykinin
3) NO

Question 4

Cells that primarily produce and release histamine

Answer 4

Mast cells and basophils

Enterochromaffin-like cells in the stomach

Question 5

Stimuli that cause mast cell release of histamine 
1)
2)
3)
4)
5)
6)

Answer 5

1) IgE crosslinking
2) C3a/C5a
3) Neuropeptides
4) Cytokines
5) Bacterial components
6) Physical trauma

Question 6

Histamine receptors

Answer 6

Four receptors: H1, H2, H3, H4.

All are GPCRs

Question 7

‘Triple response’ to histamine

Answer 7

Reddening (vasodilation), wheal (oedema from increased vascular permeability), flare (sensitisation of nerve fibres)

Question 8

Antihistamine drug action

Answer 8

Block one of the histamine receptors, most commonly H1

Question 9

Things that antihistamines can be used to treat
1)
2)
3)
4)
5)
6)
7)

Answer 9

1) Hayfever
2) Atopic dermatitis
3) Urticaria
4) Anaphylaxis, angiodema
5) Bites, stings
6) Pruritus (itching)
7) Motion sickness

Question 10

Three classes of competitive, reversible H1 antagonists

Answer 10

1) Sedative (EG: chlorpheniramine, promethazine)
2) Older non-sedative (EG: terfenadine, astemizole)
3) Newer non-sedative (EG: cetirizine, loratidine)

Question 11

Why were the older non-sedative antihistamines discontinued?

Answer 11

Terfenadine and astemizole were found to rarely cause sudden ventricular arrhythmia

Question 12

H2 receptor antagonist use

Answer 12

Treatment of peptic ulcers

Question 13

Gastric acid secretion
1)
2)
3)

Answer 13

1) Cholinergic nerve releases ACh onto enterochromaffin-like cell in stomach.
2) Cnterochromaffin-like cell releases histamine
3) H2 receptor on parietal cell binds histamine, cAMP formed, H+/K+ cotransporter activated, secreting H+ into stomach

Question 14

Bradykinin
1)
2)
3)

Answer 14

1) Autacoid
2) Local peptide mediator in pain and inflammation
3) Generated after plasma exudation during inflammation

Question 15

Bradykinin production
1)
2)
3)

Answer 15

1) Prekallikrein (inactive plasma protein) is activated by factor XII
2) Kallikrein activates high-molecular-weight kininogen
3) High-molecular-weight kininogen activates bradykinin

Question 16

Bradykinin degradation

Answer 16

Degraded by angiotensin converting enzyme (ACE), otherwise known as kininase I and II

Question 17

Bradykinin actions
1)
2)
3)

Answer 17

1) Vascular
– Dilate arterioles & venules (released PGs / NO)
– Increased vascular permeability
2) Neural
– Stimulate sensory nerve endings - pain
3) Other
– Contract uterus, airways & gut
– Epithelial secretion in airways & gut

Question 18

Bradykinin receptors

Answer 18

B1 and B2. Both GPCRs

Question 19

Example of a selective bradykinin 2 receptor

Answer 19

Icatibant. Limited clinical use

Question 20

Hereditary angiodema

Answer 20

C1-esterase inhibitor deficiency.

Leads to krallikrein overactivity

Question 21

How was the endothelium shown to have an important role in vascular tone?

Answer 21

ACh organ bath tests with vascular walls were giving different results (vasodilator in vivo, vasoconstrictor in vitro).
Helical preparations were stripping the vascular walls of endothelium. When endothelium removed, vasoconstriction occurred.

Question 22

Why does vasoconstriction occur in an organ bath when a vascular wall without endothelium is exposed to acetylcholine, but vasodilation occurs when endothelium is intact?

Answer 22

Endothelium releases vasodilatory factors (NO, prostacyclin) when exposed to ACh.
Smooth muscle (exposed in helical slice preparation) contracts when in contact with ACh

Question 23

Alternative name for NO

Answer 23

Endothelium-derived relaxant factor

Question 24

Endothelium-derived vasoactive factors

Answer 24

Vasodilatory - NO, prostacyclin, endothelium-derived hyperpolarising factor

Vasoconstrictive - Endothelin

Question 25

How is NO generated?
1)
2)
3)

Answer 25

1) Shear stress on cell, bradykinin, ACh binding to receptor
2) This stimulates Ca2+ influx, which activates nitrogen oxide synthase.
3) Nitrogen oxide synthase converts arginine to NO and citrulline
This occurs in an endothelial cell

Question 26

How does NO produce vasodilation?
1)
2)
3)
4)

Answer 26

1) Enters vascular smooth muscle cell
2) NO activates guanylate cyclase
3) GTP converted to cGMP. cGMP results in relaxation of smooth muscle.
4) Cyclic nucleotide phosphodiesterase converts cGMP to GTP.

Question 27

Three isoforms of NOS

Answer 27

1) nNOS (nerves, epithelial cells)
2) iNOS (indicible. Macrophages, smooth muscle)
3) eNOS (endothelial cells)

Question 28

NOS inhibitors

Answer 28

L-arginine analogues (L-NAME). Result in vasoconstriction, hypertension.

Question 29

Physiological role of NO
1)
2)
3)

Answer 29

1) Flow-dependent vasodilation - released in response to shear forces on blood vessel wall
2) Inhibits platelet adhesion and aggregation
3) nNOS is a neurotransmitter