Twenty-five years ago prostaglandin (PG) F2 alpha was identified as the first cyclooxygenase-derived metabolite of polyunsaturated fatty acid metabolism in the bovine central nervous system (CNS). On the other hand, 12-hydroxyeicosatetraenoic acid (12-HETE) was the first lipoxygenase product of polyunsaturated fatty acid metabolism to be identified in rat and gerbil brain. For various cyclooxygenase products of arachidonic acid metabolism a substantial body of evidence suggests a mediator role in CNS functions such as in the regulation of local blood flow, in the induction of fever and in the prevention or limitation of seizure activity. By contrast, rather limited information is available on the possible roles of lipoxygenase products of polyunsaturated fatty acid metabolism in the CNS. This review is intended to give a survey on biosynthesis, regional distribution and possible functional importance of HETEs and leukotrienes (LT) in the CNS.

Animals↗

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Prostaglandins, cyclic nucleotides and glycosaminoglycan biosynthesis in cultured fibroblasts.

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Cells, Cultured↗

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Thromboxane B2 release and 3H-noradrenaline accumulation by a synaptosomal fraction of rat brain.

Release of thromboxane B2 (TXB2) and accumulation of 3H-noradrenaline (3H-NA) by a synaptosomal fraction of rat brain were investigated. TXB2 release was temperature-dependent and was inhibited by three different TX-synthetase inhibitors: imidazole, 9,11-azoprosta-5,13-dieonic acid (AZO) and 11,9-epoxyiminoprosta-5,13-dionic acid (EPI). While high concentrations of imidazole decreased the 3H-NA accumulation in the synaptosomes significantly, AZO and EPI were ineffective. The results show that TX synthesis is not essential for 3H-NA uptake and the effect of imidazole in 3H-NA accumulation is unrelated to its inhibitory effect on the enzyme TX-synthetase.

Animals↗

PubMedDate not supplied

The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis.

We studied the action of the biologically active metabolite of molsidomine, N-morpholino-N-nitrosoamino-acetonitrile (SIN), on eicosanoid formation and functional behavior of bovine coronary arteries and human platelets in vitro. Glyceryltrinitrate (GTN) and prostaglandin (PG) I2 were used as reference compounds. SIN dose-dependently inhibited the thrombin-, collagen-, and primary ADP-induced platelet aggregation. The IC50 was in the range of 0.1-0.8 mumol/L. At these concentrations SIN also inhibited thromboxane formation, but did not influence the PGI2 biosynthesis of coronary vessels. Molsidomine itself was inactive. GTN stimulated vascular PGI2 formation, but did not modify the platelet aggregation at comparable concentrations. A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN. The IC50 amounted to 1.7 +/- 0.4 mumol/L and was in the same range as with 5,8,11,14-eicosatetraynoic acid (2.0 +/- 0.3 mumol/L). Although the results may not suggest a common mechanism of the antiaggregatory action of GTN and SIN, they provide no evidence of a similar or dissimilar mechanism of action in vascular smooth muscle.

Animals↗