33 - Local Mediators and Pharmacological Modulation Flashcards
Exosomes
Membrane-bound sacs released by cells to communicate. Can have surface proteins, some sort of signalling molecules within exosome
Why do local mediators often only act locally?
1)
2)
1) Often labile or rapidly degraded
2) Diluted too much beyond their point of release
Three important examples of local mediators
1) Histamine
2) Bradykinin
3) NO
Cells that primarily produce and release histamine
Mast cells and basophils
Enterochromaffin-like cells in the stomach
Stimuli that cause mast cell release of histamine 1) 2) 3) 4) 5) 6)
1) IgE crosslinking
2) C3a/C5a
3) Neuropeptides
4) Cytokines
5) Bacterial components
6) Physical trauma
Histamine receptors
Four receptors: H1, H2, H3, H4.
All are GPCRs
‘Triple response’ to histamine
Reddening (vasodilation), wheal (oedema from increased vascular permeability), flare (sensitisation of nerve fibres)
Antihistamine drug action
Block one of the histamine receptors, most commonly H1
Things that antihistamines can be used to treat 1) 2) 3) 4) 5) 6) 7)
1) Hayfever
2) Atopic dermatitis
3) Urticaria
4) Anaphylaxis, angiodema
5) Bites, stings
6) Pruritus (itching)
7) Motion sickness
Three classes of competitive, reversible H1 antagonists
1) Sedative (EG: chlorpheniramine, promethazine)
2) Older non-sedative (EG: terfenadine, astemizole)
3) Newer non-sedative (EG: cetirizine, loratidine)
Why were the older non-sedative antihistamines discontinued?
Terfenadine and astemizole were found to rarely cause sudden ventricular arrhythmia
H2 receptor antagonist use
Treatment of peptic ulcers
Gastric acid secretion
1)
2)
3)
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
Bradykinin
1)
2)
3)
1) Autacoid
2) Local peptide mediator in pain and inflammation
3) Generated after plasma exudation during inflammation
Bradykinin production
1)
2)
3)
1) Prekallikrein (inactive plasma protein) is activated by factor XII
2) Kallikrein activates high-molecular-weight kininogen
3) High-molecular-weight kininogen activates bradykinin
Bradykinin degradation
Degraded by angiotensin converting enzyme (ACE), otherwise known as kininase I and II
Bradykinin actions
1)
2)
3)
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
Bradykinin receptors
B1 and B2. Both GPCRs
Example of a selective bradykinin 2 receptor
Icatibant. Limited clinical use
Hereditary angiodema
C1-esterase inhibitor deficiency.
Leads to krallikrein overactivity
How was the endothelium shown to have an important role in vascular tone?
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.
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?
Endothelium releases vasodilatory factors (NO, prostacyclin) when exposed to ACh. Smooth muscle (exposed in helical slice preparation) contracts when in contact with ACh
Alternative name for NO
Endothelium-derived relaxant factor
Endothelium-derived vasoactive factors
Vasodilatory - NO, prostacyclin, endothelium-derived hyperpolarising factor
Vasoconstrictive - Endothelin
How is NO generated?
1)
2)
3)
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
How does NO produce vasodilation? 1) 2) 3) 4)
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.
Three isoforms of NOS
1) nNOS (nerves, epithelial cells)
2) iNOS (indicible. Macrophages, smooth muscle)
3) eNOS (endothelial cells)
NOS inhibitors
L-arginine analogues (L-NAME). Result in vasoconstriction, hypertension.
Physiological role of NO
1)
2)
3)
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
