Local and hormonal mediators

Question 1

What is the physiological role of NO?

Answer 1

• “Flow-dependent” vasodilatation
– NO release in response to shear forces
– Consequences for endothelial damage/dysfunction

• Inhibits platelet adhesion and aggregation
• Neurotransmitter

Question 2

Where is Histamine stored and what is the ‘triple response’?

Answer 2

Largely stored in and released from:
– Mast cells (tissues-particularly mucosal
surfaces/skin)
– Basophils (blood)
- Enterochromaffin-like cells (GIT) – regulate stomach acid secretion

Histamine ‘Triple response’

1. Reddening - vasodilation at initiating site
2. Wheal - increase vascular permeability
3. Flare - spreading response through sensory fibres

Question 3

What are some uses of H1 and H2 receptor antagonists (antihistamines)?

Answer 3

H1 antagonists (e.g. - cetirizine, loratidine) useful in treating:
– Hayfever (allergic rhinitis)
– Anaphylaxis & angiodema (adjunct to adrenaline)
– Bites & stings
– Pruritus (itching) (H4 also)
– Motion sickness

H2 antagonists (e.g. Cimetidine/Ranitidine)
-useful in treating peptic ulcers

Question 4

How do the side effects of ACE-inhibitors relate to Bradykinin?

Answer 4

Side effects: low BP and headaches.

ACE-inhibitors stop ACE (Kininase II) and therefore Bradykinin isn’t cleaved/ broken down and causes vasodilation and pain

Question 5

What makes aspirin a ‘special’ NSAID?

Answer 5

1. low dose cardio protective effect

2. production of inflammation-resolving lipoxins

Question 6

What are the pathways Arachidonic acid can be metabolised?

Answer 6

1. 2 types of cyclo-oxygenase expressed in all cells
   - constitutive (COX-1) -physiological prostaglandins (PGs)

-inducible (COX-2) gene induced by inflammatory stimuli
(eg IL-1)

2. lipoxygenase expressed in inflammatory cells -eosinophils and mast cells
   production associated with inflammation

Question 7

What are the functions of PGE2?

Answer 7

• relaxes vascular smooth muscle
• vasodilation/natriuretic - decreased BP
• hyperalgesic- sensitises nerves to painful stimuli
• pyrogenic - fever producing
• angiogenic (wound healing/tumour growth)

Question 8

Where do prostaglandins exert their effect?

Answer 8

Stable prostaglandins work locally and not systemically, broken down in the lung

Changes in structures give each PG a high specificity for different receptor types

Question 9

What are the features and functions of prostacyclins?

Answer 9

Chemically unstable half-life ~ 3 min
•Produced by endothelial cells
• reduces platelet activation
• vasodilator
•Protects against
 coronary artery disease

Question 10

What are the features and functions of thromboxane?

Answer 10

Chemically unstable half-life ~ 30 sec

• Produced by platelets
• increases platelet activation
• vasoconstrictor
• Promotes coronary artery disease

These actions oppose those of PGI2

Question 11

How do fish oils act as an anti-inflammatory agent?

Answer 11

Fish oils replace C20:4 Arachidonic acid with C20:5 EPA, so PGI3 produced still has function but TxA3 is inefficient tipping scales in favour of PGI3 (prostacyclins)