leukotriene-e4 and Shock--Septic

This study evaluated whether or not prostacyclin (PGI2) was necessary or sufficient by itself in a pathophysiologic concentration to mediate the cardiovascular dysfunction of septic shock. Anesthetized adult swine received anesthesia only (ANESTHESIA CONTROL, n = 6); graded Aeromonas hydrophila, 10(10)/mL, infusion at 0.2 mL/kg/h that increased to 4.0 mL/kg/h over 3 h (SEPTIC SHOCK CONTROL, n = 6); pathophysiologic prostacyclin infusion to match septic shock control plasma levels without bacteremia (PGI2 INFUSION, n = 6), or graded Aeromonas hydrophila plus anti-prostacyclin antibody infusion (ANTI-PGI2-Ab INFUSION, n = 5). This graded porcine bacteremia model was 100% lethal after 4 h. Cardiovascular hemodynamics, arterial blood gases, and plasma levels of arachidonate metabolites were measured at baseline and hourly over a 4-h period. The results showed that PGI2 was not a necessary mediator of impaired cardiovascular hemodynamics in graded bacteremia, as anti-PGI2 antibody infusion did not improve the cardiac index, systemic vascular resistance, or peripheral oxygen balance in septic animals. Also, PGI2 was not sufficient alone to cause the cardiovascular dysfunction of sepsis, as pathophysiologic infusion of PGI2 did not reproduce such changes in normal animals. PGI2 blockade during bacteremia significantly increased LTC4D4E4, and LTB4 whereas PGI2 infusion suppressed LTC4D4E4 concentration, suggesting that endogenous PGI2 may blunt leukotriene release during septic shock. These results indicate a complex dynamic equilibrium among prostacyclin and leukotrienes in septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Aeromonas hydrophila; Animals; Antibodies; Bacteremia; Epoprostenol; Gram-Negative Bacterial Infections; Leukotriene C4; Leukotriene D4; Leukotriene E4; Shock, Septic; Swine; Thromboxane B2

The metabolism and disposition of tritiated leukotriene C4, [3H]-LTC4, were studied in control dogs and endotoxin-treated dogs. Radioactivity was monitored in plasma, bile, and urine for 4.5 hr after an IV bolus of [3H]-LTC4. A decreased recovery of radioactivity in bile and urine was observed in the endotoxin-treated dogs. Cumulative [3H]-LTC4 metabolic patterns in bile and urine were determined by reverse-phase high-performance liquid chromatography (RP-HPLC) separation. Three primary metabolites, [3H]-LTD4, [3H]-LTE4, and a polar metabolite, (0.15-0.19)LT, accounted for most of the total bile radioactivity. The same primary metabolites were found for endotoxin-treated dogs and in similar relative amounts. [3H]-LTE4 and the polar metabolite (0.15-0.21)LT were the primary metabolites found in urine, but no N-acetyl LTE4 was found in bile or urine for either group. Plasma incubation of [3H]-LTC4 revealed heat-sensitive dipeptidase and glutamyl transpeptidase activity with significant production of [3H]-LTD4 and [3H]-LTE4 after 5- and 30-min incubation. Pharmacokinetic analysis using the two-compartment open model revealed an increased distribution phase rate constant (alpha) and distribution phase half-life [t1/2(alpha)], and decreased clearance (ClB), volume of distribution [Vd(ss) and Vd(area)] and elimination rate microconstant (Kel) of tritiated leukotrienes for endotoxin-treated dogs. This analysis along with the maintained higher plasma levels of tritiated leukotrienes, [3H]-LTs, in endotoxin-treated dogs suggests that endotoxin caused a decreased body clearance and less peripheral tissue penetration of [3H]-LTs. Collectively, these results indicate that the metabolism of LTC4 to LTD4 and LTE4, but not N-acetyl LTE4, in dogs was similar to that reported for man, pig, and monkey but dissimilar to rat. Endotoxin did not affect the types or relative amounts of metabolites found in bile or urine but appears to affect the disposition of [3H]-LTs by decreasing clearance and distribution.

Topics: Anesthesia; Animals; Bile; Chromatography, High Pressure Liquid; Dipeptidases; Dogs; Escherichia coli; gamma-Glutamyltransferase; Half-Life; Kinetics; Leukotriene E4; Male; Metabolic Clearance Rate; Penicillamine; Shock, Septic; SRS-A; Tritium

The role of lipoxygenase metabolites of arachidonic acid as inflammatory mediators of endotoxin shock remains uncertain. In this study the effect of LY171883, a selective leukotriene D4/E4 antagonist, on the hemodynamic alterations of endotoxin shock was assessed. Adult male rats were given an intraperitoneal injection of LY171883 (30 mg/kg) or vehicle 10 minutes prior to intravenous injection of endotoxin (15 mg/kg) or vehicle. Cardiac output, mean arterial pressure, and multiple organ blood flows were determined at 30 minutes after endotoxin or vehicle administration with 85Sr-radiolabeled microspheres. Cardiac output decreased from 32.1 +/- 2.7 ml/min/100 g in the control group to 16.3 +/- 2.7 ml/min/100 g in endotoxin-treated animals (P less than .05). Pretreatment with LY171883 blunted significantly (P less than .05) this fall in cardiac output (26.3 +/- 2.6 ml/min/100 g). Endotoxin reduced mean arterial pressure from 95 +/- 8 mm Hg in controls to 57 +/- 8 (P less than .05), which was not, however, different from control values in rats receiving the LTD4/E4 antagonist. There was also significant (P less than .05) blunting of the endotoxin-induced fall in blood flow to the heart, gastrointestinal tract, and kidneys in animals pretreated with LY171883. Our data demonstrate that this selective leukotriene D4/E4 antagonist has significant salutary actions in endotoxin shock and suggest that LTD4 and/or E4 mediate, in part, the acute hemodynamic sequelae of endotoxin shock.

Topics: Acetophenones; Animals; Azoles; Blood Circulation; Endotoxins; Hemodynamics; Leukotriene E4; Male; Rats; Rats, Inbred Strains; Salmonella enteritidis; Shock, Septic; SRS-A; Tetrazoles; Time Factors

The role of lipoxygenase metabolites as inflammatory mediators in endotoxic shock remains uncertain. In the present study, the effects of a selective leukotriene (LT) D4/LTE4 antagonist, LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-YL)-butoxy]-phenyl ethanone], on endotoxin-induced sequelae in the rat were assessed. LY171883 was given as a bolus (30 mg/kg i.v.) 10 min before Salmonella enteritidis endotoxin (40 mg/kg) in ketamine-anesthetized (200 mg/kg i.m.) rats, followed by an infusion (10 mg/kg/hr) starting at 30 min postendotoxin. Carotid artery blood pressures were determined at 10 min before and at intervals up to 240 minutes postendotoxin administration. Compared to shocked vehicle controls LY171883 attenuated (analysis of variance, P less than .02) the initial (0-30 min), but not the later, endotoxin-induced hypotension. LY171883 prevented completely (analysis of variance, P less than .001) the neutropenia (0-180 min), but not the thrombocytopenia induced by endotoxin. Hemoconcentration resulting from endotoxemia was reduced by LY171883 compared to the vehicle control group (P less than .02). These data demonstrate that this LTD4/LTE4 antagonist has significant salutary actions in endotoxemia and suggest that LTs may contribute to some endotoxin-induced sequelae.

Topics: Acetophenones; Analysis of Variance; Animals; Azoles; Bacterial Toxins; Blood Pressure; Endotoxins; Enterotoxins; Hematocrit; Leukotriene E4; Male; Neutropenia; Platelet Count; Rats; Salmonella enteritidis; Shock, Septic; SRS-A; Tetrazoles; Thrombocytopenia