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)
H3 located mainly in
CNS - Coupled to Gi/Go
H3 function
Auto-receptor in neurons that use histamine as a neurotransmitter
Linked to inhibition of neurotransmitter release
Ca2++ influx through voltage gated channels
Also - inhibition oof adenylyl cyclase
H4 located mainly on
Mast cells, Basophils, and eosinophils - Coupled to Gi/Go
H4 function
Linked to histamine induced chemotaxis
Thought to be really important target for suppressing inflammatory responses
Pharmacology of histamine: Cardiovascular
a. Heart - moderate rise in rate and force of contraction (h2 rise in SA conduction; reflex tachycardia)
b. Vasodilation - H1 in endothelium; H2 in sm muscle)
Pharmacology of histamine: Respiratory:
H1 mediated constriction of bronchial smooth muscle
Pharmacology of histamine: acid release in stomach
H2 mediated release from parietal cells in stomach
Pharmacology of histamine: Anaphylaxis
Hypotension and loss of fluid to the interstitial space: lowers in effective blood volume; swelling
CV effects of histamine: colocalization
CV - Have to block BOTH H1 and H2 receptors
Histamine has (direct/indirect) effects on the heart
Direct - increases rate and force of contraction
Vasodilation MOA
Action potentials in SA node
-undergoes autonomous/spontaneous action potentials - sets the rate for the heart
SA node rate is set by
Phase 4 depolarization
-fairly flat
-takes a while to get to action
In vasodilation, histamine has effect on
Depolarization
-Action potentials are coming more frequently when stimulated by histamine
Phase 4 stim is deeper - go from most depolarized voltage to voltage that will stimulate the next action potential more quickly = HIGHER RATE OF ACTION POTENTIALS
More calcium =
Greater force of contraction
