SIMVASTATIN REDUCES MORTALITY AND HEPATIC INJURY AFTER HEMORRHAGE/RESUSCITATION IN RATS
| Autor: | Fabian Bormann, Korbinian Seyboth, Christoph Czerny, Borna Relja, Dirk Henrich, Christoph Höhn, Ingo Marzi, Mark Lehnert |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Simvastatin Resuscitation Nitric Oxide Synthase Type III Neutrophils Apoptosis Hemorrhage DNA Fragmentation Critical Care and Intensive Care Medicine Text mining Animals Medicine Cytoskeleton Aldehydes Interleukin-6 business.industry Hemodynamics medicine.disease Actins Rats Liver Anesthesia Emergency Medicine Blood cholesterol Tyrosine lipids (amino acids peptides and proteins) Lipid Peroxidation Medical emergency Hydroxymethylglutaryl-CoA Reductase Inhibitors business medicine.drug |
| Zdroj: | Shock. 34:46-54 |
| ISSN: | 1073-2322 |
| DOI: | 10.1097/shk.0b013e3181cd8d05 |
| Popis: | Statins are established in the prevention and therapy of chronic cardiovascular diseases because of inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A), thus lowering blood cholesterol levels. However, their cholesterol-independent effects include regulation of Rho/Rho-kinases (ROCK) and eNOS, proteins centrally involved in various models of acute inflammation. Therefore, we tested the hypothesis that simvastatin confers protection after rat hemorrhage/resuscitation (H/R) and wanted to elucidate the mechanisms involved. Fifty-two female Lewis rats (180-250 g) were pretreated with simvastatin 5 mg/kg per day or vehicle for 6 days (i.p.). Then, rats were hemorrhaged to a mean arterial pressure of 30 +/- 2 mmHg for 60 min and resuscitated. Control group underwent surgical procedures without H/R. Two hours after resuscitation, tissues were harvested. Mortality was assessed 72 h after H/R. Simvastatin pretreatment increased survival after H/R from 20% to 80%. Serum alanine aminotransferase after H/R increased 2.2-fold in vehicle as compared with simvastatin-treated rats. Histopathological analysis revealed decreased hepatic necrosis in simvastatin-treated rats after H/R. Hepatic oxidative (4-hydroxynonenal) and nitrosative (3-nitrotyrosine) stress, inflammatory markers (serum IL-6 and hepatic infiltration with polymorphonuclear leukocytes), and actin cytoskeleton rearrangements were decreased after simvastatin pretreatment compared with vehicle-treated rats after H/R. Simvastatin increased eNOS and heme oxygenase 1 expression and eNOS activation. Expression of Rho/Rho-kinase and myosin phosphatase targeting subunit, Thr-MYPT1, a marker for Rho-kinase activity, decreased after simvastatin treatment compared with vehicle-treated rats after H/R. Simvastatin pretreatment exerts beneficial effects in this model of acute inflammation by supporting protective mechanisms that are important for hepatic microcirculation after H/R. |
| Databáze: | OpenAIRE |
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