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Statins inhibit 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase, the rate limiting step in cholesterol synthesis. They are, therefore, used clinically to lower cholesterol and prevent atherosclerosis. Statins have beneficial effects on multiple organ systems. Some of these effects are found in the absence of significant changes in cholesterol levels. Polyunsaturated fatty acids also inhibit HMG-CoA reductase and have many of the same beneficial effects of statins. Four statins (mevastatin, lovastatin, simvastatin and atorvastatin) have been tested in rat liver cells for their effect on arachidonic acid (AA) release and prostaglandin I2 production induced in the presence of lactacystin and 12-O-tetradecanoylphorbol-13-acetate. Each statin stimulated release of AA and induced prostaglandin I2 production. Mevalonate, the product of HMG-CoA reductase, did not reduce the stimulation observed in the presence of simvastatin indicating that HMG-CoA reductase activity is not involved. In view of the multiple biologic properties of AA, the AA released as a result of the action of the statins may play a role in some of the pharmacological effects attributed to these drugs.