Ex. 3 - Histamines 1

Question 1

Where is histamine stored? What is it released in response to?

Answer 1

Granules;
Antigens and Cell lysis

Question 2

an important mediator of inflammation

Answer 2

Histamine

Question 3

Histamine is synthesized in _ and _

Answer 3

Mast cells and basophils

Question 4

Histamine is (activated/inactivated) fairly rapidly by a number of enzymes

Answer 4

Inactivated

Question 5

N-methylatoin of histamine

Answer 5

Inactivated at receptors

Question 6

Oxidation of histamine

Answer 6

Oxidizes from primary amine to carboxylic acid to inactivate

Question 7

Distribution of mast cells

Answer 7

High numbers in skin, nose, mouth, lungs and intestinal mucosa
wherever body is touching environment

Question 8

Storage granules

Answer 8

Histamine is complexed with: sulfated-polysaccharides, heparin sulfate chondroitin sulfate, and proteases

Question 9

Non-mast cell histamines

Answer 9

Nerve terminals in some areas of brain (neurotransmitter)
Fundus of stomach - specialized cells store histamine for stimulation and acid secretion

Question 10

Causes of histamine release from mast cells and basophils:

Answer 10

Antigen mediated
Non-antigen mediated

Question 11

Antigen mediated release

Answer 11

Binding of antigen (allergens) to antibodies bound to the cell surface (IgE) other inflammatory agents are also release (kinins, serotonin, leukotrienes, prostaglandins)

Question 12

Non-antigen mediated release

Answer 12

Thermal or mechanical stress cytotoxic agents - venoms, various drugs, (e.g. high dose morphine)

Question 13

Mechanism of histamine release

Answer 13

1. Binding of IgE antibodies to FcEr
2. Binding of antigen to IgE antibodies
3. Clustering of FcER receptors
4. Influx of CA2+ via Ca2+ release activated channels (CRAC)
   ((Influx of calcium that drives exocytosis of these granules)

Question 14

Drugs that prevent histamine release:

Answer 14

Cromolyn Sodium
Rx - Mastocytosis (oral)
OTC - allergic rhinitis (nasal spray)
Nedocromil
Rx- allergic conjunctivitis (eye drops)

Question 15

Beta adrenergic agonists can - while AcH can -

Answer 15

inhibit antigen-induced histamine;
Stimulate histamine release from mast cells

Question 16

There are _ histamine receptor subtypes; all are -

Answer 16

Four; G-protein coupled

Question 17

H1 receptor

Answer 17

Distributed throughout the CV, Respiratory systems, G.I. smooth muscle
**Linked to phosphoinositol pathway, activation causes contraction of smooth muscle

Question 18

H1 MOA

Answer 18

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

Question 19

Main points of H1

Answer 19

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

Question 20

H1 receptor: vasodilation

Answer 20

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

Question 21

H1 receptor: stimulation of sensory nerves

Answer 21

Hist + H1 (in cutaneous or nasal mucosal nerve endings)
Causes: Sneezing and itching (pruitus)

Question 22

H2 receptor placement

Answer 22

Distributed in CV system, and Gi smooth muscle, and stomach

Question 23

H2 receptors

Answer 23

Present in vascular smooth muscle
Stimulation of cAMP causes relaxation of smooth muscle
Linked to relaxation of vasc. smooth muscle and gastric secretion

Question 24

H1 and H2 colocalization:

Answer 24

Vascular smooth muscle and endothelium
H1 in vascular endothelium - NO increase
increase in contraction of endothelial cells
H2 in vascular muscle - relaxation (vasodilation)

Question 25

H3 located mainly in

Answer 25

CNS - Coupled to Gi/Go

Question 26

H3 function

Answer 26

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

Question 27

H4 located mainly on

Answer 27

Mast cells, Basophils, and eosinophils - Coupled to Gi/Go

Question 28

H4 function

Answer 28

Linked to histamine induced chemotaxis
Thought to be really important target for suppressing inflammatory responses

Question 29

Pharmacology of histamine: Cardiovascular

Answer 29

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)

Question 30

Pharmacology of histamine: Respiratory:

Answer 30

H1 mediated constriction of bronchial smooth muscle

Question 31

Pharmacology of histamine: acid release in stomach

Answer 31

H2 mediated release from parietal cells in stomach

Question 32

Pharmacology of histamine: Anaphylaxis

Answer 32

Hypotension and loss of fluid to the interstitial space: lowers in effective blood volume; swelling

Question 33

CV effects of histamine: colocalization

Answer 33

CV - Have to block BOTH H1 and H2 receptors

Question 34

Histamine has (direct/indirect) effects on the heart

Answer 34

Direct - increases rate and force of contraction

Question 35

Vasodilation MOA

Answer 35

Action potentials in SA node
-undergoes autonomous/spontaneous action potentials - sets the rate for the heart

Question 36

SA node rate is set by

Answer 36

Phase 4 depolarization
-fairly flat
-takes a while to get to action

Question 37

In vasodilation, histamine has effect on

Answer 37

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

Question 38

More calcium =

Answer 38

Greater force of contraction