salicylates and Sepsis

Sepsis is associated with an increase in reactive oxygen species (ROS), however, the precise role of ROS in the septic process remains unknown. We hypothesized that treatment with EUK-134 (manganese-3-methoxy N,N'-bis(salicyclidene)ethylene-diamine chloride), a compound with superoxide dismutase and catalase activity, attenuates the vascular manifestations of sepsis in vivo. Pigs were instrumented to measure cardiac output and blood flow in renal, superior mesenteric and femoral arteries, and portal vein. Animals were treated with saline (control), lipopolysaccharide (LPS; 10 µg·kg-1·h-1), EUK-134, or EUK-134 plus LPS. Results show that an LPS-induced increase in pulmonary artery pressure (PAP) as well as a trend towards lower blood pressure (BP) were both attenuated by EUK-134. Renal blood flow decreased with LPS whereas superior mesenteric, portal and femoral flows did not change. Importantly, EUK-134 decreased the LPS-induced fall in renal blood flow and this was associated with a corresponding decrease in LPS-induced protein nitrotyrosinylation in the kidney. PO2, pH, base excess and systemic vascular resistance fell with LPS and were unaltered by EUK-134. EUK-134 also had no effect on LPS-associated increase in CO. Interestingly, EUK-134 alone resulted in higher CO, BP, PAP, mean circulatory filling pressure, and portal flow than controls. Taken together, these data support a protective role for EUK-134 in the renal circulation in sepsis.

Topics: Animals; Antioxidants; Cardiac Output; Femoral Artery; Lipopolysaccharides; Mesenteric Artery, Superior; Organometallic Compounds; Portal Vein; Reactive Oxygen Species; Renal Circulation; Salicylates; Sepsis; Sus scrofa

Manganese-salen complexes (Mn-Salen), including EUK-8 [manganese N,N'-bis(salicylidene)ethylenediamine chloride] and EUK-134 [manganese 3-methoxy N,N'-bis(salicylidene)ethylenediamine chloride], have been reported to possess combined superoxide dismutase (SOD) and catalase mimetic functions. Because of this SOD/catalase mimicry, EUK-8 and EUK-134 have been investigated as possible therapeutic agents in neurological disorders resulting from oxidative stress, including Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis. These actions have been explained by the ability of the Mn-Salen to remove deleterious superoxide (O(2)(-)) and H(2)O(2). However, in addition to oxidative stress, cells in models for neurodegenerative diseases may also be subjected to damage from reactive nitrogen oxides (nitrosative stress), resulting from elevated levels of NO and sister compounds, including peroxynitrite (ONOO(-)). We have been examining the interaction of EUK-8 and EUK-134 with NO and ONOO(-). We find that in the presence of a per-species (H(2)O(2), ONOO(-), peracetate and persulphate), the Mn-Salen complexes are oxidized to the corresponding oxo-species (oxoMn-Salen). OxoMn-Salens are potent oxidants, and we demonstrate that they can rapidly oxidize NO to NO(2) and also oxidize nitrite (NO(2)(-) to nitrate (NO(2)(-)). Thus these Mn-Salens have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O(2)(-), H(2)O(2), ONOO(-) and NO to benign species: O(2), H(2)O, NO(2)(-) and NO(3)(-).

Topics: Animals; Astrocytes; Catalase; Cattle; Dose-Response Relationship, Drug; Ethylenediamines; Hydrogen Peroxide; Liver; Manganese; Manganese Compounds; Models, Chemical; Nitric Oxide; Organometallic Compounds; Oxidative Stress; Oxygen; Rats; Rats, Wistar; Salicylates; Sepsis; Superoxide Dismutase; Time Factors

An 81-year-old woman with unintentional salicylate intoxication presented with features of sepsis, abdominal pain, and tenderness. Laparotomy was performed to rule out acute cholecystitis. Anesthesia was complicated by severe hypercarbia despite hyperventilation, and progressive cardiovascular and neurologic deterioration postoperatively. The adverse neurologic, respiratory, and hepatic effects of abdominal surgery and general anesthesia probably potentiated salicylate toxicity and increased patient morbidity. Anesthesiologists should be aware of the protean manifestations of salicylate poisoning and consider it as a cause of "medical abdomen."

Topics: Abdominal Pain; Aged; Anesthesia, General; Anti-Inflammatory Agents, Non-Steroidal; Drug Overdose; Female; Humans; Salicylates; Sepsis

Reactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain.

Topics: Animals; Cell-Free System; Cyanides; Electron Transport; Hydrogen Peroxide; Hydroxybenzoates; Hydroxyl Radical; Iron; Male; Mitochondria, Liver; Oxidative Stress; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rotenone; Salicylates; Salicylic Acid; Sepsis; Subcellular Fractions; Succinates; Succinic Acid

Topics: Adult; Aged; Cortisone; Endoscopy; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Peptic Ulcer Hemorrhage; Phenylbutazone; Renal Dialysis; Salicylates; Sepsis

Topics: Anti-Infective Agents, Local; Bismuth; Dosage Forms; Drug Contamination; Drug Industry; Drug Storage; Emollients; Emulsions; Humans; Ointment Bases; Ointments; Pharmaceutic Aids; Phenols; Salicylates; Salmonella Infections; Sepsis; Sterilization; Tablets; Technology, Pharmaceutical; Temperature; Time Factors; Water Microbiology

Endotoxin [lipopolysaccharide (LPS)] from four Gram-negative bacteria injected i.v. delayed absorption of drugs administered in solution by gastric tube to mice and rats. Salicylate and guinine absorption was delayed at LPS doses from 50 to 400 mug/kg. Salicylate absorption was delayed by LPS when drug was given by gastric tube, while LPS did not affect drug levels when salicylate was given i.p. or intraduodenally. Bethanechol prevented the LPS effect and LPS pretreatment also protected against delayed absorption. LPS- treated rats retained more drugs in their stomachs after 30 minutes and their plasma salicylate levels were lowered. Everted intestinal sacs from LPS-treated rats transferred salicylate as well as controls. Thus, LPS delays gastrointestinal drug absorption solely by retarding gastric emptying. Escherichia coli urinary tract infection did not reproduce LPS delay of drug absorption, but the effects of systemic bacteria were similar to those of endotoxemia.

Topics: Animals; Bacteria; Bethanechol Compounds; Duodenum; Endotoxins; Escherichia coli Infections; Intestinal Absorption; Lipopolysaccharides; Male; Mice; Polysaccharides, Bacterial; Quinine; Rats; Salicylates; Sepsis; Species Specificity; Time Factors; Toxemia; Urinary Tract Infections