(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Multiple-Organ-Failure

Multiple organ dysfunction resulting from hemorrhagic shock (HS) and subsequent resuscitation was mediated by several inflammatory factors such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10). The present study was designed to investigate the protective effects of fluvastatin on these mediators after HS in rats.. The experimental rats were randomly divided into three groups. The vehicle group received only vitamin K without HS, the HS-control group received vitamin K and HS, and the HS-experimental group received both vitamin K and fluvastatin (1mg/kg) before HS. HS was produced by bleeding from a femoral arterial catheter to remove 60% of total blood volume (6ml/100g BW) over 30min. The mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 12h after the start of blood withdrawal. The biochemical parameters, including arterial blood gas, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), creatine phosphokinase (CPK), and lactate were obtained at 30min before induction of HS and at 0, 1, 3, 6, 9 and 12h after HS. Equal volume of normal saline was given to replace blood volume loss. Cytokine levels including TNF-alpha and IL-10 in serum were measured at 1h after HS. Kidney, liver, lung and small intestine were removed for pathology examination at 48h after HS.. HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, lactate, TNF-alpha and IL-10 levels, and also induced metabolic acidosis and decreased MAP in rats. Pre-treatment with fluvastatin was found to improve survival rate, preserved MAP, decreased the markers of organ injury, suppressed the release of TNF-alpha and increased IL-10 after HS in rats.. Pre-treatment with fluvastatin can suppress the release of serum TNF-alpha and can also increase serum IL-10 level to protect HS-induced multi-organ damage in rats.

Topics: Animals; Antifibrinolytic Agents; Antioxidants; Blood Gas Analysis; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Fluvastatin; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interleukin-10; Male; Multiple Organ Failure; Rats; Rats, Inbred WKY; Shock, Hemorrhagic; Treatment Outcome; Tumor Necrosis Factor-alpha; Vitamin K

Sepsis is a severe inflammatory disorder that may lead to multiple organ failure. Lipopolysaccharide (LPS) is associated with Gram-negative sepsis and can activate monocytes and macrophages to release pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and anti-inflammatory mediator such as interleukin-10 (IL-10). In this present study, we used fluvastatin, a HMG-CoA reductase inhibitor, to study its effects upon LPS-induced endotoxic shock in conscious rats.. The experiments were designed that rats received an intravenous injection of 1mg/kg fluvastatin followed 10min later, by an intravenous injection of 10mg/kg Klebsiella pneumoniae LPS, the latter inducing endotoxic shock amongst conscious rats. Subsequently, the levels of certain biochemical variables and cytokines in serum were then measured during the ensuing 48-h period following sepsis. These included total cholesterol (TCH), triglyceride (TG), blood urea nitrogen (BUN), creatinine (Cre), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), aspartate transferase (GOT), alanine transferase (GPT), tumor necrosis factor-alpha, interleukin-10 and nitric oxide.. LPS significantly increased blood TG, BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-10 and NO levels but decreased the blood TCH level. Pretreatment of test rats with fluvastatin decreased blood levels of certain markers of organ injury, suppressed the release of TNF-alpha and increased IL-10, and NO levels following LPS treatment. Fluvastatin did not affect the blood TCH and TG level subsequent to the development of sepsis.. Pre-treatment with fluvastatin suppresses the release of plasma TNF-alpha, increases plasma IL-10, and NO production, and decreases the levels of markers of organ injury associated with endotoxic shock, so ameliorating LPS-induced organ damage amongst conscious rats.

Topics: Alanine Transaminase; Analysis of Variance; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Cholesterol; Creatine Kinase; Creatinine; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Injections, Intravenous; Interleukin-10; L-Lactate Dehydrogenase; Lipopolysaccharides; Male; Multiple Organ Failure; Nitric Oxide; Rats; Rats, Wistar; Triglycerides; Tumor Necrosis Factor-alpha