Ex. 3 - Histamines 1 Flashcards
Where is histamine stored? What is it released in response to?
Granules;
Antigens and Cell lysis
an important mediator of inflammation
Histamine
Histamine is synthesized in _ and _
Mast cells and basophils
Histamine is (activated/inactivated) fairly rapidly by a number of enzymes
Inactivated
N-methylatoin of histamine
Inactivated at receptors
Oxidation of histamine
Oxidizes from primary amine to carboxylic acid to inactivate
Distribution of mast cells
High numbers in skin, nose, mouth, lungs and intestinal mucosa
wherever body is touching environment
Storage granules
Histamine is complexed with: sulfated-polysaccharides, heparin sulfate chondroitin sulfate, and proteases
Non-mast cell histamines
Nerve terminals in some areas of brain (neurotransmitter)
Fundus of stomach - specialized cells store histamine for stimulation and acid secretion
Causes of histamine release from mast cells and basophils:
Antigen mediated
Non-antigen mediated
Antigen mediated release
Binding of antigen (allergens) to antibodies bound to the cell surface (IgE) other inflammatory agents are also release (kinins, serotonin, leukotrienes, prostaglandins)
Non-antigen mediated release
Thermal or mechanical stress cytotoxic agents - venoms, various drugs, (e.g. high dose morphine)
Mechanism of histamine release
- Binding of IgE antibodies to FcEr
- Binding of antigen to IgE antibodies
- Clustering of FcER receptors
- Influx of CA2+ via Ca2+ release activated channels (CRAC)
((Influx of calcium that drives exocytosis of these granules)
Drugs that prevent histamine release:
Cromolyn Sodium
Rx - Mastocytosis (oral)
OTC - allergic rhinitis (nasal spray)
Nedocromil
Rx- allergic conjunctivitis (eye drops)
Beta adrenergic agonists can - while AcH can -
inhibit antigen-induced histamine;
Stimulate histamine release from mast cells
There are _ histamine receptor subtypes; all are -
Four; G-protein coupled
H1 receptor
Distributed throughout the CV, Respiratory systems, G.I. smooth muscle
**Linked to phosphoinositol pathway, activation causes contraction of smooth muscle
H1 MOA
Activation of H1 receptors by histamine will activate phospholipase C
This stimulates IP3 and DAG
IP3 causes release of calcium from intracellular storage
Leads to calcium calmodulin dependent processes, including phosphorylation of MLC = contraction
Main points of H1
H1 - activates Gq mediated signaling through PLC
Increase in intracellular Ca+ via IP3 receptors
H1 receptor leads to activation of this pathway = contraction of smooth muscle
H1 receptor: vasodilation
In vascular endothelial cells
Endothelial cells produce NO
-Stimulates NO release
NO diffuses to vascular smooth muscle - stimulates cGMP within vascular smooth muscle
DECREASE ca2+ - causes relaxation of smooth muscle
H1 receptor: stimulation of sensory nerves
Hist + H1 (in cutaneous or nasal mucosal nerve endings)
Causes: Sneezing and itching (pruitus)
H2 receptor placement
Distributed in CV system, and Gi smooth muscle, and stomach
H2 receptors
Present in vascular smooth muscle
Stimulation of cAMP causes relaxation of smooth muscle
Linked to relaxation of vasc. smooth muscle and gastric secretion
H1 and H2 colocalization:
Vascular smooth muscle and endothelium
H1 in vascular endothelium - NO increase
increase in contraction of endothelial cells
H2 in vascular muscle - relaxation (vasodilation)
