The Role of Eicosanoids

Arachidonic acid comprises part of the membrane phospholipid pool and is released in a single-step reaction by activated phospholipase A2 (PLA2). PLA2 can be activated by various agonists, such as norepinephrine, angiotensin II, cytokines, and free radicals (107,108). Activated PLC and phospholipase D are also able to release free AA but not directly. Rather, they generate lipid products that contain AA (diacylglycerol and phosphatidic acid, respectively), which can be released subsequently by monoacylglycerol- and diacylglycerol-lipases. Once released, free AA has 3 possible fates: reincorporation into phospholipids, diffusion outside the cell, and metabolism. Metabolism is carried out by 3 distinct enzyme pathways: cyclooxygen-ase, lipoxygenases, and CYP. Metabolism of free AA by cyclooxygenases and lipoxygenases leads to the formation of prostaglandins, thromboxanes, and leukotrienes, with important roles in the regulation of vascular tone and inflammation (109). Cyclooxygenase- and lipoxygenase-catalyzed AA metabolism is well characterized, and both these pathways are targets of approved drugs. In contrast, our knowledge of metabolism of AA by CYP enzymes is more limited, although recent efforts in this area hold the promise that new drug targets will also emerge from this pathway.

Cerebral blood vessels synthesize vasoconstrictive prostaglandins (prostaglandin F2a, E2, A1, and B2, and the powerful vasodilator prostacyclin PGI2). In addition, cerebral vessels are constricted by thromboxane A2 and B2. Some evidence suggests that prostaglandin synthesis is significantly altered after SAH, in that production of vasoconstricting prostaglandins and thromboxanes is increased and synthesis of PGI2 is decreased (110,111). However, prostaglan-din synthesis inhibitors, such as aspirin, are not very effective in reversing vasospasm, and indomethacin might even exacerbate vasospasm (112,113). These agents typically have multiple actions, which might include the inhibition of vasodilator pathways.

Leukotrienes, the products of the lipoxygenase pathway, are synthesized only in very small amounts in experimental models of vasospasm, and no changes are detectable in CSF leukotriene-levels post-SAH (114). Additionally, even in large concentrations, leukotrienes are only weak vasoconstrictors and are, therefore, unlikely to play an important role in vasospasm ( 115 ).

Recent studies have drawn attention to the role of 20-HETE in the development of cerebral vasospasm and demonstrated that 20-HETE plays an important role in both the acute and delayed phases of experimental cerebral vasospasm (116,117). 20-HETE is a potent cerebral vasoconstrictor that is produced by the metabolism of AA by CYP4A enzymes in cerebral arteries (118). 20-HETE activates PKC, Ras, tyrosine kinase, MAPK, and rho/rho kinase pathways, promotes calcium entry by depolarizing cerebral arteries secondary to blockade of KCa channels, and increases Ca2+ influx by activating L-type Ca2+ channels in the cerebral vasculature (117). Furthermore, 20-HETE contributes to the vasoconstrictor responses to endothelin, angiotensin II, serotonin, vasopressin, and norepinephrine (117). The concentration of 20-HETE in CSF increases markedly after SAH, and inhibitors of the synthesis or actions of 20-HETE prevent the acute fall in cerebral blood flow after SAH and fully reverse delayed vasospasm in the rat (116,117). It is, therefore, possible that elevated production of 20-HETE might represent the final common pathway that leads to cerebral vasospasm, if such a pathway indeed exists.

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