Local hormones
Bi1100en Hormones – Cellular and Molecular Mechanisms
Eicosanoids
Histamine
Serotonin
▪ derived from C20 polyunsaturated fatty acids (PUFAs)
- arachidonic acid (AA; 20: 4n-6)
- eicosapentaenoic acid (EPA; 20: 5n-3)
- dihomo-γ-linolenic acid (DGLA; 20: 3n-6)
▪ precursors in the cytoplasmic and nuclear membrane > released by
phospholipase A2 > synthesis of eicosanoids by cyclooxygenases (COX),
lipoxygenases (LOX) and other enzymes
Eicosanoids
Eicosanoids - synthesis
▪ the synthesis takes place mainly in: endothelial cells
leukocytes
platelets
kidneys
▪ biosynthesis in all cell types except red blood cells
▪ eicosanoids are not stored in the cells
▪ four main groups:
leukotrienes (LOX)
prostaglandins (COX)
prostacyclins (COX)
thromboxanes (COX)
hepoxilins (LOX)
lipoxins (LOX)
epi-lipoxins (LOX)
epoxyeicosatrienoic acid (cytochrome P450 epoxygenase)
isoprostanes (cytochrome P450 epoxygenase)
▪ the basis of the COX pathway are prostaglandins G (PGG2) and H (PGH2)
prostanoids
Eicosanoids - synthesis
wikipedia.org
Eicosanoids - synthesis
▪ evolutionarily conserved
▪ production is neural- and hormonal-regulated (increase in Ca2+ levels, cell
swelling, etc.)
▪ rapid degradation > transport to the long distances is limited
▪ specific effect on target cells near the site of their synthesis
▪ they can also act within intracellular signaling pathways
▪ bound to G protein-coupled receptors (stimulation or inhibition of cAMP
synthesis; cleavage of phosphatidylinositol-4,5-bisphosphate and release of
Ca2+) or nuclear receptors (peroxisome proliferator-activated receptor,
PPARγ)
Eicosanoids – mode of action
▪ eicosanoids act even in very low concentrations (like hormones)
▪ short half-life, therefore acting on autocrine and paracrine level (unlike
classical hormones)
▪ effects in the body vary not only by species of eicosanoid, but also according
to which receptors they can bind at a given tissue
Biological role of eicosanoids:
▪ mediate the inflammatory response, especially in the joints (rheumatoid
arthritis), skin (psoriasis) and eyes
▪ mediating pain and fever
▪ participate in the regulation of blood pressure
▪ participate in the regulation of coagulation (e.g. platelet aggregation)
▪ mediate immune responses (chemotaxis, nodulation and more)
▪ affect kidney function (vasodilation and regulation of glomerular filtration)
▪ participates in the control of some processes in the reproductive system (e.g.
childbirth)
▪ participate in sleep cycle regulation
Eicosanoids – mode of action
Eicosanoids – mode of action
Non-steroidal antiinflammatory
drugs
(NSAID)
▪ hormone and neurotransmitter
▪ derived from the amino acid histidine (histidine decarboxylase)
▪ produced mainly by nerves, tissue mast cells and basophilic granulocytes,
enterochromaffin (ECL) cells in the stomach
▪ during the immune response, its synthesis is stimulated by antigen-antibody
complexes (IgE) and activated complement
▪ its production is inhibited by adrenaline, PGE2 and histamine itself
▪ primarily acts locally, but in response to the allergen may cause a wholebody
reaction (anaphylactic shock)
▪ histamine receptors (H1- H4) coupled to G proteins
Histamine
▪ stimulates vasodilation and increases vascular permeability > edema >
lower blood pressure (despite being stimulated via H2 receptors which
strengthen heartbeat and increase heart rate)
▪ vasodilation induced directly or indirectly through the promotion of nitric oxide
production in the endothelium
▪ affects smooth muscle (contractions of the uterus, bronchi and intestine)
▪ stimulates the parietal cells of the stomach to produce hydrochloric acid
▪ causes irritation of peripheral nerves > itching
▪ histamine causes the symptoms of allergic reaction type I (hives, hay fever)
Therapy
▪ antihistamines H1 (allergic reactions), antihistamines H2 (gastric ulcers)
▪ administration of sympathomimetics
Histamine – mode of action
▪ derived from the amino acid tryptophan (5-hydroxytryptamine)
▪ hormone and neurotransmitter
▪ production in the CNS (10 %), enterochromaffin intestinal cells (90 %),
platelets, proximal renal tubules and bronchi
Action:
▪ it is involved mainly in the transmission of nerve impulses
▪ mood control („hormone of happiness")
▪ serotonergic neurons in the brain probably play an important role in
alternating circadian rhythms and inducing sleep (part of melatonin
synthesis)
▪ stimulates smooth muscle contractions (uterus, bronchi, intestine, blood
vessels)
▪ promotes platelet aggregation and thus blood clotting
▪ in relation to the above mentioned, serotonin has a great impact on injuries
▪ can cause headaches by acting on blood vessels (migraine)
Serotonin