Local Hormonal Mediators Flashcards
What are exosomes?
- small membrane-bound vesicles released by cells
- contain mRNA and interference RNA
- can regulate tissue function by binding to cells and influencing transcription
- found in plasma and urine
What are the methods of chemical signalling between cells?
- Release of molecules
- neurotransmitters via wired networks
- hormones (broadcast)
- local mediators (vicinity, shouting)
- exosomes
- Membrane-bound molecules
- immune system (cellular neighbours, antigen presentation)
What restricts local mediators?
- labile - readily self-destruct
- rapidly metabolised
- diluted quickly beyond biologically active range close to their site of release
What are autacoids?
- local mediators
- brief duration
- act near site of synthesis
What are some of the modulatory functions of local mediators?
- smooth muscle tone/length
- glandular secretion
- permeability (vascular, airway)
- sensory nerves (pain and itch)
Histamine is found in
mast cells and basophils
How is histamine released?
- common mediator released in atopic hypersensitivity (atopy/allergy) reactions
- atopy = increased IgE
- exposure to allergen leads to cross linking of IgE and receptors on mast cell surface
- triggers degranulation (exocytosis) of histamine
What stimuli trigger histamine release?
- antigen via IgE
- complement fragments C3a/C5a (known as anaphylatoxins)
- neuropeptides
- cytokines and chemokines
- bacterial components
- physical trauma
What are the histamine receptors?
- four: H1, H2, H3, H4
- all are GPCRs
- all have selective agonists and antagonists
What is the ‘triple response’?
- classic vasoactive response of histamine
- skin reddening (vasodilation)
- wheal (localised increase in vascular permeability causing oedema, fluid exudate)
- flare (spreading response through sensory fibres causes distal reddening through broader vasodilation due to neuropeptide release)
What is the general function of H1 receptor antagonists?
Antihistamines
What are H1 receptor blockers used to treat?
antihistamines
- hayfever (allergic rhinitis)
- atopic dermatitis (w/gluccocorticoids)
- urticaria (hives)
- anaphylaxis and angiodema (w/adrenaline)
- bites and stings
- pruritus (H4 receptors also play a role)
- motion sickness (via CNS)
- can directly prevent degranulation of mast cells
What are the classes of H1 receptor antagonists?
- sedative (cause drowsiness)
- e.g. chlorpheniramine, promethazine
- non-sedative (poor entry to CNS)
- e.g. terfenadine, astemizole
- cause rare, sudden ventricular arrhythmias so withdrawn from market
- newer non-sedative agents (replaced above)
- e.g. cetirizine, loratidine
Chlorpheniramine, promethazine
sedative H1 receptor antagonists (antihistamines)
terfenadine, astemizole
non-sedative H1 receptor antagonists (antihistamines)
**removed from market due to ventricular arrhythmias**
cetirizine, loratidine
newer non-sedative H1 receptor antagonists (antihistamines)
(reduced risk of unwanted cardiac effects)
What are enterochromaffin-like (ECL) cells?
- mast-like cells that release histamine onto pareital cells to regulate secretion of stomach acid
- tf peptic ulcers used to be treated with H2 receptor antagonists, now known to be caused by helicobacter pylori
Cimetidine/ranitidine
- H2 receptor antagonists
- previously used for tx of peptic ulcers
- blocks H2 receptor on parietal cells
- histamine from ECL cells cannot induce production of acid
What is the function of peptide/proteins as chemical signals?
- derived from AAs
- hundreds that serve regulatory roles
- hormonal: act through blood e.g. insulin
- cytokines, cheomikines
- vasoactive intestinal peptide
- neurotransmitters: e.g. neuropeptide Y
- local: e.g. bradykinin
Bradykinin functions in
- local peptide mediator in pain and inflammation
How is bradykinin activated and synthesized?
- triggered by plasma exudation during inflammation
- leakiness of vessels during inflammation activates coagulation cascade
- Hageman factor (XII) leaves bloodstream and becomes activ
- cleaves prekillikrein (plasma protein) to active kallikrein
- kallikrein activtes high-molecular weight kininogen (plasma protein) to cleave bradykinin
How is bradykinin degraded?
- cleaved rapidly (local mediator)
- converted into inactive form by Kininase I and II
- Kininase II = Angtiotensin converting enzyme (ACE)
- converted into inactive form by Kininase I and II
What are the actions of bradykinin?
- vascular
- dilates arterioles and venules by triggering release of prostaglandins and NO from vascular endothelial cells
- increased vascular permeability
- neural
- stimulate sensory nerve endings causing pain
- other
- uterine, airway, and gut contraction
- epithelial secretion in airways and gut
What are the receptors for bradykinin?
B1 & B2 (GPCRS)
B1 - expressed in pathophysiology (trauma, burns, etc.)
B2 - expressed in all healthy tissue
Icatibant
- only clinical selective B2 (bradykinin) receptor antagonist
- tx of hereditary angioedema
*
What is hereditary angiodema, and how is it treated?
- C1esterase inhibitor deficiency (a serine protease inhibitor/SERPIN)
- -C1esterase means there is no brake on killikrein to reduce bradykinin production
- elevated bradykinin leads to vasodilation in the deeper tissues, causing angioedema
- Tx: icatibant, selective bradykinin B2 receptor antagonist blocks effect of bradykinin
NO causes
vasodilation of endothelium
What are the endothelium-derived relaxing factors?
- Prostacylcin (PGI2)
- NO (aka endothelium derived relaxinf vactor, EDRF)
- endothelium derived hyperpolarizing factor (EDHF)
What is the endothelium derived contraction factor?
Endothelin
Prostacyclin causes
vasodilation of endothelium
Endothelin causes
constriction of endothelium
How is NO produced?
- ACh and bradykinin receptors on endothelial cells or mechanical shear stress cause increase in intracellular calcium
- this stimulates nitric oxide synthase (NOS) to its active form
- converts arginine to citrulline & NO
- NO is a gas and tf can then rapidly diffuse out of the cell
How does NO produce vasodilation of vascular smooth muscle?
- NO diffuses from endothelial cells to vascular smooth muscle cells
- activates guanylate cyclase
- GTP –> cGMP
- cGMP causes relaxation of the blood vessel
How is NO function regulated in the vascular smooth muscle cell?
- cyclic nucleotide phosphodiesterase (PDE) metabolises to GMP, preventing it from causing smooth mucle relaxation
- e.g. PDE blockage in erectile tissue enhances relaxation to facilitate erection i.e. drugs like sildenafil (viagra)
What are the 3 isoforms of NOS?
- nNOS (nerves, epithelial cells)
- iNOS (inducible i.e. in inflammatory response - macrophages, smooth muscle
- eNOS (endothelial cells)
N-nitro-L-arginine methyl ester (L-NAME)
- NOS inhibitor
- L-arginine analog
What is the effect of NOS inhibitors?
- Vasoconstriction
- Hypertension
What is the function of NO?
- homeostatic regulator of blood pressure and vascular tone
- inhibits platelet adhesion and aggregation
- can act as a neuro/co-transmitter
Nitrovasodilators (e.g. GTN/nitroglycerin) act by
liberating NO, causing vasodilation
