Origin and metabolism. The eicosanoids, prostaglandins, thromboxane, prostacyclin, and leukotrienes, are formed in the organism from arachi-donic acid, a C20 fatty acid with four double bonds (eicosatetraenoic acid). Arachidonic acid is a regular constituent of cell membrane phospholipids; it is released by phospholipase A2 and forms the substrate of cyclooxygenases and lipoxygenases.

Synthesis of prostaglandins (PG), prostacyclin, and thromboxane proceeds via intermediary cyclic endoperoxides. In the case of PG, a cyclopentane ring forms in the acyl chain. The letters following PG (D, E, F, G, H, or I) indicate differences in substitution with hydrox-yl or keto groups; the number subscripts refer to the number of double bonds, and the Greek letter designates the position of the hydroxyl group at C9 (the substance shown is PGF2a). PG are primarily inactivated by the enzyme 15-hydroxyprostaglandindehydrogenase. Inactivation in plasma is very rapid; during one passage through the lung, 90% of PG circulating in plasma are degraded. PG are local mediators that attain biologically effective concentrations only at their site of formation.

Biological effects. The individual PG (PGE, PGF, PGI = prostacyclin) possess different biological effects.

Nociceptors. PG increase sensitivity of sensory nerve fibers towards ordinary pain stimuli (p. 194), i.e., at a given stimulus strength there is an increased rate of evoked action potentials.

Thermoregulation. PG raise the set point of hypothalamic (preoptic) ther-moregulatory neurons; body temperature increases (fever).

Vascular smooth muscle. PGE2 and PGI2 produce arteriolar vasodilation; PGF2a, venoconstriction.

Gastric secretion. PG promote the production of gastric mucus and reduce the formation of gastric acid (p. 160).

Menstruation. PGF2a is believed to be responsible for the ischemic necrosis of the endometrium preceding menstruation. The relative proportions of individual PG are said to be altered in dys-menorrhea and excessive menstrual bleeding.

Uterine muscle. PG stimulate labor contractions.

Bronchial muscle. PGE2 and PGI2 induce bronchodilation; PGF2a causes constriction.

Renal blood flow. When renal blood flow is lowered, vasodilating PG are released that act to restore blood flow.

Thromboxane A2 and prostacyclin play a role in regulating the aggregabil-ity of platelets and vascular diameter (p. 150).

Leukotrienes increase capillary permeability and serve as chemotactic factors for neutrophil granulocytes. As "slow-reacting substances of anaphylaxis," they are involved in allergic reactions (p. 326); together with PG, they evoke the spectrum of characteristic inflammatory symptoms: redness, heat, swelling, and pain.

Therapeutic applications. PG derivatives are used to induce labor or to interrupt gestation (p. 126); in the therapy of peptic ulcer (p. 168), and in peripheral arterial disease.

PG are poorly tolerated if given systemically; in that case their effects cannot be confined to the intended site of action.

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Pain stimulus

A. Origin and effects of prostaglandins

Pain stimulus

A. Origin and effects of prostaglandins

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