Eicosanoids


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Eicosanoids

A family of naturally occurring, biologically active substances derived from 20 carbon polyunsaturated fatty acids such as arachidonic acid. Members of the family include prostaglandins, thromboxanes, leukotrienes, and epoxy-eicosatrienoic acids (EETs). Functioning as local hormones, they are synthesized and exert their biological actions in the same tissue. Many have physiological and pathological effects on the cardiovascular, pulmonary, reproductive, and digestive systems.

Physiologically and pathologically, eicosanoids are local hormones. They are synthesized and exert their action in a tissue, and only certain eicosanoids are made by the cells of a tissue. As a result, the action of an eicosanoid is usually discrete and related to the physiological demands of the tissue.

The prostaglandins, leukotrienes, TXA2, and anandamide act by binding to and activating membrane receptor proteins. Distinct receptors have been identified for many eicosanoids. The existence of receptor subgroups explains how some eicosanoids such as PGE2 have multiple actions.

The prostaglandins and TXA2 have several actions that are necessary for maintaining normal homeostasis and organ integrity. PGE2 and PGI2 are potent vasodilators. These prostaglandins are synthesized in the blood vessel in response to vasoconstrictors and antagonize their effects. This action protects the organ from intense vasoconstriction and maintains nutritive blood flow. They also inhibit gastric acid secretion and may exert other cellular protective effects. In their absence, gastric ulcers develop. TXA2 is made principally by platelets. It causes vasoconstriction and promotes platelet aggregation. These actions prevent excessive blood loss when a blood vessel is damaged or severed. PGI2 is made by the blood vessel wall and has the opposite effects. It prevents intravascular platelet aggregates from forming and obstructing blood flow. The balance between the proaggregatory or vasoconstrictor action of TXA2 and the antiaggregatory or vasodilator action of PGI2 is critical to cardiovascular homeostasis. PGF2α contracts uterine smooth muscle. With menstruation and destruction of the uterine lining, arachidonic acid is released and metabolized to PGF2α. Contraction of the uterine smooth muscle by PGF2α contributes to the pain associated with menstruation. In pregnancy, an increase in prostaglandin synthesis is a major determinant of the onset of labor.

Increased synthesis of PGE2 and PGI2 mediates the vasodilation and pain sensitization associated with inflammation and arthritic conditions. Inhibitors of cyclooxygenase-1 and -2 (important catalysts in the synthesis of prostaglandins) such as aspirin and ibuprofen relieve the signs and symptoms of inflammation. However, they also block the constitutive, homeostatic functions of the prostaglandins by blocking cyclooxygenase-1, which can result in renal failure and gastric ulcers. Selective cyclooxygenase-2 inhibitors such as celecoxib are anti-inflammatory without the deleterious effects on homeostatic functions of the prostaglandins.

The leukotrienes are synthesized by leukocytes, and they also serve as inflammatory mediators. LTB4 is chemotactic and promotes leukocyte aggregation. Thus, it attracts other inflammatory cells to the site of inflammation and sequesters them. LTC4, LTD4, and LTB4 increase capillary permeability, causing the leakage of fluid and protein from the vasculature into the tissue. This contributes to the swelling associated with inflammation. LTC4 and LTD4 also cause bronchiolar constriction and increase mucus formation in the airways. These actions are thought to contribute to bronchial asthma. Inhibitors of 5-lipoxygenase and leukotriene receptor antagonists are useful in treating inflammation and bronchial asthma.

The EETs and 20-HETE (hydroxyeicosatetraenoic acid) are involved in the regulation of vascular tone and organ blood flow. In the blood vessel, EETs are synthesized by the endothelial cells in response to vasodilator hormones. The EETs diffuse to the adjacent smooth muscle cells and exert their action. They open potassium channels and hyperpolarize the smooth muscle cell membrane. This results in vasodilation. Thus, EETs serve as mediators of vasodilation. 20-HETE is made by smooth muscle cells in response to increases in intravascular pressure. It is a mediator of myogenic tone in blood vessels. In the blood vessel wall, 20-HETE and the EETs are counterregulatory mechanisms that control blood flow.

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