Local Hormonal Mediators Flashcards

1
Q

What are exosomes?

A
  • 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
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2
Q

What are the methods of chemical signalling between cells?

A
  • Release of molecules
    • neurotransmitters via wired networks
    • hormones (broadcast)
    • local mediators (vicinity, shouting)
    • exosomes
  • Membrane-bound molecules
    • immune system (cellular neighbours, antigen presentation)
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3
Q

What restricts local mediators?

A
  • labile - readily self-destruct
  • rapidly metabolised
  • diluted quickly beyond biologically active range close to their site of release
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4
Q

What are autacoids?

A
  • local mediators
  • brief duration
  • act near site of synthesis
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5
Q

What are some of the modulatory functions of local mediators?

A
  • smooth muscle tone/length
  • glandular secretion
  • permeability (vascular, airway)
  • sensory nerves (pain and itch)
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6
Q

Histamine is found in

A

mast cells and basophils

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7
Q

How is histamine released?

A
  • 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
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8
Q

What stimuli trigger histamine release?

A
  • antigen via IgE
  • complement fragments C3a/C5a (known as anaphylatoxins)
  • neuropeptides
  • cytokines and chemokines
  • bacterial components
  • physical trauma
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9
Q

What are the histamine receptors?

A
  • four: H1, H2, H3, H4
  • all are GPCRs
  • all have selective agonists and antagonists
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10
Q

What is the ‘triple response’?

A
  • 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)
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11
Q

What is the general function of H1 receptor antagonists?

A

Antihistamines

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12
Q

What are H1 receptor blockers used to treat?

A

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
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13
Q

What are the classes of H1 receptor antagonists?

A
  • 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
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14
Q

Chlorpheniramine, promethazine

A

sedative H1 receptor antagonists (antihistamines)

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15
Q

terfenadine, astemizole

A

non-sedative H1 receptor antagonists (antihistamines)

**removed from market due to ventricular arrhythmias**

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16
Q

cetirizine, loratidine

A

newer non-sedative H1 receptor antagonists (antihistamines)

(reduced risk of unwanted cardiac effects)

17
Q

What are enterochromaffin-like (ECL) cells?

A
  • 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
18
Q

Cimetidine/ranitidine

A
  • 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
19
Q

What is the function of peptide/proteins as chemical signals?

A
  • 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
20
Q

Bradykinin functions in

A
  • local peptide mediator in pain and inflammation
21
Q

How is bradykinin activated and synthesized?

A
  • 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
22
Q

How is bradykinin degraded?

A
  • cleaved rapidly (local mediator)
    • converted into inactive form by Kininase I and II
      • Kininase II = Angtiotensin converting enzyme (ACE)
23
Q

What are the actions of bradykinin?

A
  • 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
24
Q

What are the receptors for bradykinin?

A

B1 & B2 (GPCRS)

B1 - expressed in pathophysiology (trauma, burns, etc.)

B2 - expressed in all healthy tissue

25
Q

Icatibant

A
  • only clinical selective B2 (bradykinin) receptor antagonist
  • tx of hereditary angioedema
    *
26
Q

What is hereditary angiodema, and how is it treated?

A
  • 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
27
Q

NO causes

A

vasodilation of endothelium

28
Q

What are the endothelium-derived relaxing factors?

A
  • Prostacylcin (PGI2)
  • NO (aka endothelium derived relaxinf vactor, EDRF)
  • endothelium derived hyperpolarizing factor (EDHF)
29
Q

What is the endothelium derived contraction factor?

A

Endothelin

30
Q

Prostacyclin causes

A

vasodilation of endothelium

31
Q

Endothelin causes

A

constriction of endothelium

32
Q

How is NO produced?

A
  • 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
33
Q

How does NO produce vasodilation of vascular smooth muscle?

A
  • NO diffuses from endothelial cells to vascular smooth muscle cells
  • activates guanylate cyclase
    • GTP –> cGMP
  • cGMP causes relaxation of the blood vessel
34
Q

How is NO function regulated in the vascular smooth muscle cell?

A
  • 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)
35
Q

What are the 3 isoforms of NOS?

A
  • nNOS (nerves, epithelial cells)
  • iNOS (inducible i.e. in inflammatory response - macrophages, smooth muscle
  • eNOS (endothelial cells)
36
Q

N-nitro-L-arginine methyl ester (L-NAME)

A
  • NOS inhibitor
  • L-arginine analog
37
Q

What is the effect of NOS inhibitors?

A
  • Vasoconstriction
  • Hypertension
38
Q

What is the function of NO?

A
  • homeostatic regulator of blood pressure and vascular tone
  • inhibits platelet adhesion and aggregation
  • can act as a neuro/co-transmitter
39
Q

Nitrovasodilators (e.g. GTN/nitroglycerin) act by

A

liberating NO, causing vasodilation