Actions and Pathophysiological Roles of Leukotrienes

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Chapter: Essential pharmacology : Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor

The straight chain lipoxygenase products of arachidonic acid are produced by a more limited number of tissues (LTB4 mainly by neutrophils; LTC4 and LTD4—the cysteinyl LTs—mainly by macrophages), but probably they are pathophysiologically as important as PGs.


ACTIONS AND PATHOPHYSIOLOGICAL ROLES

 

Leukotrienes

 

The straight chain lipoxygenase products of arachidonic acid are produced by a more limited number of tissues (LTB4 mainly by neutrophils; LTC4 and LTD4—the cysteinyl LTs—mainly by macrophages), but probably they are pathophysiologically as important as PGs.

 

CVS and blood

 

LTC4 and LTD4 injected i.v. evoke a brief rise in BP followed by a more prolonged fall. The fall in BP is not due to vasodilatation because no relaxant action has been seen on blood vessels. It is probably a result of coronary constriction induced decrease in cardiac output and reduction in circulating volume due to increased capillary permeability. These LTs markedly increase capillary permeability and are more potent than histamine in causing local edema formation. LTB4 is highly chemotactic for neutrophils and monocytes; this property is shared by HETE but not by other LTs. Migration of neutrophils through capillaries and their clumping at sites of inflammation in tissues is also promoted by LTB4.

 

Role

LTs are important mediators of inflammation. They are produced (along with PGs) locally at the site of injury. While LTC4 and D4 cause exudation of plasma, LTB4 attracts the inflammatory cells which reinforce the reaction. 5HPETE and 5HETE may facilitate local release of histamine from mast cells.

 

Smooth Muscle

 

LTC4 and D4 contract most smooth muscles. They are potent bronchoconstrictors and induce spastic contraction of g.i.t. at low concentrations.

 

They also increase mucus secretion in the airways.

 

Role

The cysteinyl LTs (C4 and D4) are the most important mediators of human allergic asthma. They are released along with PGs and other autacoids during AG: AB reaction in the lungs. In comparison to other mediators, they are more potent and are metabolized slowly in the lungs, exert a long lasting action. LTs may also be responsible for abdominal colics during systemic anaphylaxis.

 

Afferent Nerves

 

Like PGE2 and I2, the LTB4 also sensitizes afferents carrying pain impulses— contributes to pain and tenderness of inflammation.

 

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