Histamine and 5-HT

• Histamine:

  • An imidazole ring (pKa = 5.74) with an amino group (pKa = 9.80)
  • Synthesis in mast cells, upregulated in stress and infections by histidine carboxylase
  • Vaccines can trigger histamine release
  • Metabolism via methylation and carboxylation by N-methyltransferase and MAO B, or carboxylation and addition to ribose by diamine oxidase

  
• Storage of histamine:

  • Lung = 15 mcg/g
  • Skin = 6 - 8 mcg/g
  • Gut = 60 - 80 mcg/g
  • Stomach = 10 mcg/g
  • Mast cell = 3 - 4 pg/cell
• Mast cells:

  • Contain up to 1000 granules
  • Granules contain histamine bound to a proteoglycan core (e.g., heparin)
  • Other proteolytic enzymes include tryptase and chymase
  • Activation causes granules to fuse with cell membrane and release contents

  
• There are several mechanisms of histamine release:

  1. IgE dependent release
  2. Other stimuli
  3. Non-specific release
• IgE dependent release: IgE on cell surface binds to mast cell via receptors when exposed to allergens. IgE is crosslinked and the mast cell granules are released. Associated with symptoms of allergic disease.
• Other stimuli for histamine release include bacterial products such as LPS, complement peptides such as C3a and C5a.

  • Involves specific receptors on mast cell surface
  • Histamine release during bacterial infections initiates and inflammatory response which recruits other elements of the immune system
• Non-specific release of histamine: a number of basic drugs such as morphine and tubocurarine release histamine by non-receptor actions. Histamine is released following trauma to tissues (UV radiation, burns, changes in osmolarity).
• Histamine receptors:

  • H1: Cardiovascular system, smooth muscle and peripheral nerves
  • H2: regulates gastric acid in stomach, increases rate and output of the heart
  • H3: found in CNS
  • H4: found on inflammatory cells
• Actions of H1:

  • Vasodilation (redness/heat)
  • Increased vascular permeability (swelling)
  • Stimulation of peripheral nerves (pain/itching)
  • Smooth muscle contraction (bronchial, GI and reproductive contraction)
• The effects of histamine on the cardiovascular system include an increase in heart rate, force of contraction, dilation of arterioles causing a fall in peripheral resistance, constriction of veins/arteries and dilation of capillaries.

  • Small doses cause a drop in peripheral resistance = drop in blood pressure
  • Large doses cause a profound decrease in blood pressure and loss of capillary fluid which can cause circulatory collapse (anaphylaxis)

  
• Histamine gives the wheal-and-flare reaction when injected into the skin. This gives the typical action of histamine (redness, pain/itch, blanching and swelling)
• Mepyramine: H1 antagonist. Side effects include drowsiness and effects on cholinergic receptors. Newer H1 agonists such as cetirizine have improved effects. Can be used for allergies, local anaesthetic, sedative actions and motion sickness.
• Actions of H2:

  • Stimulates gastric acid secretion
  • Regulates cardiac output and rate
  • Modulates actions of immune cells
• Regulation of gastric acid (H2):

  • Muscarinic receptors and gastrin receptors trigger the release of histamine
  • H2 receptor is on the parietal cell
  • Binding triggers proton pump responsible for the production of gastric acid
  • Over production of acid can lead to peptic ulcer

  
• Treatment of peptic ulcer:

  • Antigastrin drugs to control mast cells or by blocking H2 receptors
  • Prostaglandins that prevent action of the proton pump
• Histamine stimulates isolated heart preparations to increase rate and force of contraction.

  • This is by direct action on the cardiac muscle or indirect via release of noradrenaline
  • H2 receptors found on lymphocytes providing negative feedback (inhibits release from degranulating mast cells)
• Cimetidine: H2 receptor antagonist. Inhibits CYP450 and can retard metabolism of drugs including anticoagulants and tricyclic antidepressants (strengthening of drug effect).
• Actions of H3:

  • Histamine acts as neurotransmitter, with histaminergic neurones in the hypothalamus
  • Release in the CNS follows distinct circadian pattern with release only in the day
• There are no H3 receptor antagonists in clinical use, however thioperamide is used in research of H3 receptors. Potential use of antagonists could be to control sleep cycles and sedation, as well as water intake and thermoregulation.
• Actions of H4:

  • On inflammatory cells, regulate cytokine networks in the inflammatory response
  • Agonists/antagonists are not fully elucidated
• Mast cells are often associated with tumours.

  • Could be facilitating tumour development with heparin increasing angiogenesis
  • Could be part of host defence against tumour
• Growing foetuses contain and produce substantial amounts of histamine, with the placenta producing large amounts of diamine oxidase.

  • Histamine has been assumes to contribute to embryo-uterine interactions due to its vasoactive, differentiation and growth-promoting properties
• 5-hydroxytryptamine (5-HT, serotonin):

  • Found in the CNS, GI tract and in platelets (as storage)
  • Different levels of serotonin cause conditions/diseases
  • Dietary sources include bananas, strawberries, pineapples and tomatoes (does not affect physiological levels)
• 5-HT is synthesised by hydration of tryptophan by tryptophan hydroxylase, then decarboxylation by L-aromatic acid decarboxylase.

  
• Metabolism of 5-HT is conversion from amine to aldehyde, then oxidation to acid by MAO and aldehyde dehydrogenase.

  
• Storage of 5-HT:

  • Synthesised in CNS and enterochromaffin cells
  • 90% stored in the gut
  • Taken up by platelets as they pass through intestinal circulation
  • Average adult contains 10 mg of 5-HT
• Fenfluramine: appetite suppressant that causes depleted 5-HT levels in the CNS.
• Ecstasy (3,4-methylenedioxy methamphetamine): causes release of 5-HT followed in a drop in tissue 5-HT.
• 5-HT1 receptors:

  • Found in CNS
  • Activation results in neural inhibition and vasocontraction
  • Important in mood/behaviour, thermoregulation, feeding and sleep
  • Sumatriptan is an agonist - no antagonists are in clinical use
• 5-HT2 receptors:

  • Found in CNS and in periphery
  • Agonists include LSD
  • Antagonists include methysergide and ketotifen. These can affect other receptors including alpha-adrenoceptors and histamine receptors
• Lysergic acid diethylamine (LSD): agonist at CNS receptors causing hallucinations, but antagonist at periphery. Inhibits 5-HT neurons of the raphe nuclei, alters perception and precipitates attacks in schizophrenia patients.
• 5-HT3 receptors:

  • Found in peripheral nervous system evoking pain
  • Found in brain where they are involved in the vomiting reflex
  • Antagonists such as ondansetron are antiemetics used during chemotherapy (may be anxiolytic)
• 5-HT4 receptors:

  • Found in CNS but main role is in regulating GI motility
  • Agonists such as tegaserod are used to relieve bloating and constipation related to IBS
• In migraines, 5-HT is known to cause vasocontraction in cerebral arteries and found in urine of patients with migraines.
• In the gut, 5-HT stimulates GI motility directly and indirectly (enteric neurons) as well as sympathetic activity.

  • Can act via release of NO from endothelial cells inhibiting NAdr release from sympathetic nerve terminals

  
• Injection of 5-HT leads to an initial rise in blood pressure as the large vessels constrict followed by a fall due to subsequent dilation of arterioles.