Arachidonic acid releasing causes

D2R causes a potentiation of calcium-evoked arachidonic acid release through G-protein-dependent mechanisms involving PKC in a range of cells (Felder et al., 1991 Kanterman et al., 1991 Piomelli et al., 1991 Nilsson et al., 1998). 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

Calcitriol modulates the maturation of chondrocytes via a cell surface receptor linked to phospholipase and protein kinase C in response to calcitriol, there are rapid changes in arachidonic acid release from, and reincorporation into, membrane phospholipids, and increased synthesis of prostaglandins Ei and E2 (Boyan et al., 1999). 24-Hydroxycalcidiol also modulates the maturation of chondrocytes, acting via cell surface receptors linked to phospholipase D, causing inactivation of both protein kinase C and MAP kinases, thus... 

In a human lung epithelial cell line, in which histamine increased the intracellular calcium concentration and the formation of eicosanoids, this response was antagonized by the histamine Hi receptor antagonist diphenhydramine but unaffected by the H2 receptor antagonist cimetidine. Fenspiride inhibited Hi receptor-induced calcium increase. Histamine also caused a biphasic increase in arachidonic acid release, which was inhibited by fenspiride. This study suggests a further mechanism that would promote antiinflammatory and bronchodilator properties. 

In several different models, treatment of cultured cells with anandamide as well as other cannab-inoids results iu increased arachidonic acid release and eicosanoid biosynthesis. Wartmaim et al. (1995) observed such an effect and gave evidence that MAP kinase contributes to this response. Exposure of Wl-38 hbroblasts to anandamide causes increased MAP kinase activity and increases the phosphorylation of cytoplasmic phospholipase A2 (cPLA2) resulting in its activation and the... 

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

The generation of radicals from lipids appear to be dependent on the abstraction of hydrogen by other radicals. Consistent with this idea is the observation that either lipid peroxidation or anoxia can cause a release of free arachidonic acid fix>m culture cells, and this release can be blocked by antioxidants (Braughler et al., 1985, 1988). 

With respect to vasodilation, niacin-elicited vasodilation requires the activation of GPR109A in skin Langerhans cells [34,35], which then triggers the release of arachidonic acid from membrane phospholipids and its subsequent metabolism to PGD2. The production of PGD2 then activates DPI receptors in dermal blood vessels to cause vasodilation [36]. 

The formation of nitric oxide in microsomes results in the inhibition of microsomal reductase activity. It has been found that the inhibitory effect of nitric oxide mainly depend on the interaction with cytochrome P-450. NO reversibly reacts with P-450 isoforms to form the P-450-NO complex, but at the same time it irreversibly inactivates the cytochrome P-450 via the modification of its thiol residues [64]. Incubation of microsomes with nitric oxide causes the inhibition of 20-HETE formation from arachidonic acid [65], the generation of reactive oxygen species [66], and the release of catalytically active iron from ferritin [67],... 

An immediate reaction occurs within seconds to minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade. Mediators of immediate hypersensitivity include histamine, leukotrienes, prostaglandin, tryptase, and kinins. These mediators cause vasodilation, increased vascular permeability, and production of nasal secretions. Histamine produces rhinorrhea, itching, sneezing, and nasal obstruction. 

In addition to the importance of Ca2+, PLA2 activity is also regulated by lipocortin (also termed lipomodulin), which is a 40-kDa protein. The inhibitory effect of lipocortin is regulated by its phosphorylation status, acting as an inhibitor of the enzyme when in the dephosphorylated state. Upon cell activation (e.g. by fMet-Leu-Phe), the lipocortin becomes phosphorylated, and PLA2 activity (usually detected as the release of arachidonic acid) increases. Protein kinase C can cause this phosphorylation, and so activation of this kinase may lead to the relief of PLA2 inhibition via phosphorylation of lipocortin. Thus, elevations in the levels of intracellular Ca2+ and production of DAG (required for protein kinase C activation) may co-ordinately activate PLA2. 

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

Triethanolamine has been clinically tested with other model irritant compoimds for potency to stimulate signal release of proinflammatory mediators in hrnnan skin in order to find biomarkers of irritancy. Neat or aqueous triethanolamine was applied to the lower arm of 12 male volimteers after 24 h, suction blister fluid specimens were taken from the site of treated skin. Triethanolamine caused no significant increase in arachidonic acid and prostaglandin concentrations in suction blister fluid samples, in... 

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed in Chapter 18, the cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. 

Stimulated platelets release arachidonic acid rapidly from their phospholipids, apparently as a result of activation of phospholipase A2. The released arachidonate can in turn be metabolized to endoperoxides and thromboxane A2 (Chapter 21). These compounds are also potent activators of platelets and cause a self-activating or autocrine effect.1) While PAF has a beneficial function, it can under some conditions contribute in a dangerous way to inflammation and to allergic responses including anaphylaxis,) asthmag and cold-induced urticaria.1 Although the effect of PAF is separate from those of histamine and of leukotrienes, these agents may act cooperatively to induce inflammation.1... 

Monocyte-macrophages are the only principal cells of the immune system that can synthesize all the eicosanoids. T and B lymphocytes are interesting exceptions to the general rule that all nucleated cells produce eicosanoids. However, in a B lymphoma cell line, there is non-receptor-mediated uptake of LTB4 and 5-HETE. Interaction between lymphocytes and monocyte-macrophages may cause the lymphocytes to release arachidonic acid from their cell membranes. The arachidonic acid is then used by the monocyte-macrophages for eicosanoid synthesis. In addition to these cells, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, PMNs, and endothelial cells. 

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