Dr. L. Hough - 08/07/2014
Terms in this set (29)
Where is the major source of histamine?
1. Mast Cells.
What are the characteristics of mast cells?
1. Associated with connective tissue throughout the body.
2. Large cells characterized by metachromasia due to the presence of proteoglycans such as heparin.
3. There are two families, the "Connective Tissue" and "Mucosal" mast cell.
What is the major source of histamine in the blood?
2. They are metachromatic, containing a heparin-like compound.
How is histamine stored mast cells and what is it's rate of synthesis and metabolism?
1. Histamine within mast cells is believed to be tightly bound to vesicles.
2. It exhibits a slow rate of synthesis and metabolism (Slow turnover).
Where is "Non-Mast Cell" Histamine found and what specific properties does it have?
1. It is found in the brain and gastric mucosa as well.
2. The turnover rate for histamine in these tissues is very rapid, in contrast to that of the mast cell.
3. Recent studies show that non-mast cell histamine resides in neurons, vascular endothelium, and in endocrine-like cells of some tissues.
What is induced, or "Nascent" Histamine?
1. Induced, or nascent, histamine is not stored in tissues, but under certain circumstances the biosynthesis of histamine can be provoked.
2. Macrophages and platelets may mediate the synthesis.
What is histamine formed from and what enzyme is associated with this reaction?
1. Almost all of the histamine found in tissue is formed from the essential amino acid L-histidine by the action of the enzyme histidine decarboxylase.
2. It uses pyridoxal phosphate as a cofactor.
3. Histidine decarboxylase is highest in tissues with high hisamine turnover, such as gastric mucosa and brain.
What are the two pathways used for histamine metabolism?
1. Oxidation via diamine oxidase.
2. Methylation via histamine-N-methyl transferase (most important).
What is the the final product involved in the Methylation pathway for histamine metabolism?
1. Histamine methytransferase forms methylhistamine which is oxidized by MAO to form methylimidazole acetic acid.
2. This compound is the major urinary metabolite of histamine.
3. It can be used as an index to check abnormalities to histamine synthesis or release.
What are the receptors for histamine and which are the most important?
1. H1, H2, H3, and H4.
2. H1 and H2 are the most important.
What effect does histamine have in the skin and what are the probable receptors involved?
1. "Triple response" (I.e. bug bite)
2. H1 and H2.
What effect does histamine have in the resistance vessels and what are the probable receptors involved?
1. Rapid vasodilation - H1.
2. Slow vasodilation - H2.
What is special about the histamine induction of vasodilation in resistance vessels for the H1 receptor?
1. The H1 induced relaxation of vascular smooth muscle requires the presence of intact endothelial cells, which are believed to release NO, which causes vasodilation, as a result of H1 stimulation.
What effect does histamine have in the heart and what are the probable receptors involved?
1. Atria - +chonotropic, +inotropic - H2.
2. Ventricles - decreased fibrilation threshold - H2.
What effect does histamine have in the Bronchiolar smooth muscle and what are the probable receptors involved?
1. Contraction - H2.
What effect does histamine have in the gastric mucosa and what are the probable receptors involved?
1. Increased acid and pepsin output - H2.
What is the triple response seen when histamine affects the skin?
1. A small red spot forms at site due to direct dilation of the terminal arterioles.
2. A "flare" which is a red flush large than the red spot due to stimulation of a local axon reflex which case a discharge of vasodilating efferent nerves.
3. A "wheal" of the same diameter of the red spot results from edematous fluid that exudes from the gaps created in the lining of the venules by the action of histamine in separating the endothelial cells.
What is the clinical use for Histamine?
1. There is no justifiable therapeutic use for histamine.
What is the mechanism of activation for the H1 receptor?
1. It is linked to phospholipase C which leads to intracellular synthesis if IP3 and DAG.
2. IP3 elevates intracelluar cytoplasmic calcium levels leading to contraction of smooth muscle.
3. Linked to these actions by Gq protein.
What is the mechanism of activation for the H2 receptor?
1. Increases cyclic AMP synthesis via adenylate cyclase in the heart, gastric mucos, adipocytes, and brain.
2. All of histamines H2 effects are though to occur via cyclic AMP production.
3. Linked to these actions by Gq protein.
Where are H3 receptors found and what purpose do they serve?
1. Known to exist in the central and peripheral nervous system.
2. Act as an autoreceptor that inhibits it's own release from brain.
3. H3 antagonists may play a role in treating sleep disorders, dementias, or obesity.
Where are H4 receptors found and what purpose do they serve?
1. Found on mast cells and other immune-related bone marrow derived cells of the immune system.
2. Modulation of inflammation is related to activation of H4 receptors.
What role does histamine have in Gastric Secretion?
1. It seems likely that histamine is the final common mediator of gastric acid secretion.
2. H2 receptors turn it on, H2 blockers turn acid secretion down.
What role does histamine have in CNS transmission?
1. Histamine serves a neurotransmitter function in the brain.
2. Histamine synthesizing nerve fibers arise from a small group of cell bodies in the tuberomammillary region, join the medial forebrain bundle and project to most telencephalic structures.
3. Histamine plays a role in cognition and wakefullness.
What are the two types of Histamine release?
1. Immunological or specific histamine release.
2. Non-Immunological or Non-Specific histamine release.
What are the steps involved int the Allergic (Specific, Immunological) release of Histamine from Mast Cells?
1. first exposure to antigenic required (sensitization) which produces antigen specific antibodies which bind mast cells.
2. Subsequent exposure to antigen cross-links mast cell-bound IgEs. activating histamine release.
3. Release requires intracellular Ca2+ and energy.
What is true regarding the release of factors released from mast cells?
1. Many factors are released by antigen exposure to mast cells, in addition to histamine.
2. The biological effects of antigen-evoked histamine release are not the same as those of histamine, and histamine antagonists do not completely prevent the effects of antigens on mast cells.
What is the mechanism of Non-Immunological (Non-specific) histamine release and what are some substances that can cause this effect?
1. Hundreds of small molecular weight, basic drugs can release histamine from mast cells but the mechanism is unknown.
2. Compound 48/80, Narcotics (codeine), neuromuscular blockers (curare, gallamine), contrast media (iopanoic acid, etc), and other can all cause non-immunologic histamine release.
What are the four pathological problems that histamine is associated with?
1. Urticaria Pigmentosa and Systemic Mastocytosis - disorders of mast cell growth, same symptoms as produced by histamine poisoning.
3. Seasonal Rhinitis and Pollenosis.
4. Inflammation - earlier mediator of acute inflammatory response via vasodilatory and increased permeability actions.