Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Cell-free hemoglobin solutions can scavenge nitric oxide and therefore increase mean arterial pressure (MAP). The present study investigated the effects of a continuous low-dose infusion of modified hemoglobin during ovine hyperdynamic sepsis. 13 sheep received a continuous infusion of live Pseudomonas aeruginosa bacteria for 48 h. Animals that survived the first 24 h of sepsis (n=12) were randomly assigned either to a treatment group that received 20 mg x kg(-1) x h(-1) pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) for 20 h or to a control group that received the same volume of the vehicle for 20 h. ⋯ No differences in regional blood flow were seen between groups. Bacterial counts in the spleen and kidney were lower in the treatment group than in the control group. Continuous low-dose infusion of PHP can normalize systemic vascular resistance and MAP for long periods without deterioration of regional blood flow or bacterial clearance.
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Overproduction of nitric oxide (NO) upon expression of inducible NO synthase (iNOS) may be responsible for refractory hypotension in septic shock. Whereas high levels of NOS activity have been documented in experimental models of endotoxemia or intravenous challenge with Escherichia coil, much less is known concerning tissue models of Gram-negative infection. We examined NO production (measured as the accumulation of plasma NO3- + NO2-) in a murine model of Gram-negative peritonitis. ⋯ In control in vitro experiments, macrophages from IFN-gammaR- or TNFR55-deficient mice, while failing to respond to IFN-gamma or TNF-alpha, respectively, produced high levels of NO under appropriate stimulation. When challenged intraperitoneally with E. coli, IFN-gammaR- or TNFR55-deficient mice exhibited similar levels of bacteremia and NO production as their wild-type controls. These data thus suggest that enhanced NO production during focal Gram-negative infection may occur in the absence of signaling through either IFN-gammaR or TNFR55.
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Although cardiac function is depressed during endotoxic shock, it remains controversial whether the ventricular contractility and structure are altered during sepsis. To resolve this issue, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). At 2, 5, and 10 h after CLP (i.e., the early, hyperdynamic stage of sepsis) or 20 h after CLP (the late, hypodynamic stage of sepsis, based on the depressed tissue perfusion), in vivo left ventricular contractility parameters such as maximal rate of the left ventricular pressure increase (+dP/dtmax) and decrease (-dP/dtmax), maximal rate of "pressure-normalized" change in ventricular pressure (dP/dtmax/P), and ventricular peak systemic pressure were determined using a Digi-Med Heart Performance Analyzer. ⋯ Although focal and moderate hypertrophy as well as expanded intermyocyte junctions could be observed occasionally, myocardial cells did not appear to be compromised at 20 h after CLP. Thus, the transition from the hyperdynamic to hypodynamic circulation during sepsis does not appear to be due to any depression in myocardial function because cardiac contractility and structure are not compromised even during the late, hypodynamic stage of sepsis. However, further investigation is required to determine whether cardiac function is depressed at the terminal stage of polymicrobial sepsis.
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The aim of the present study was to investigate the role of poly(ADP-ribose) synthetase in a nonseptic shock model, wherein oxyradicals, nitric oxide, and peroxynitrite are known to play a crucial role in the inflammatory process. DNA single-strand breakage and activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Here we investigated whether peroxynitrite production and PARS activation are involved in cytotoxicity in macrophages collected from rats subjected to zymosan-induced shock. ⋯ In vivo treatment with 3-aminobenzamide (10 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) or nicotinamide (50 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) significantly inhibited the decrease in mitochondrial respiration and the activation of PARS, and partially restored the cellular level of NAD+. In a separate group of experiments, in vivo pretreatment with NG-nitro-L-arginine methyl ester, a nonselective inhibitor of nitric oxide synthesis (10 mg/kg intraperitoneally, 15 min before zymosan administration), reduced peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, and the loss of cellular levels of NAD+. Our study suggests that formation of peroxynitrite and subsequent activation of PARS may alter macrophage function in inflammatory processes and inhibition of nitric oxide, and that PARS may be a novel pharmacological approach to prevent cell injury in inflammation.
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We sought to understand the mechanism of metabolic acidosis that results in acute resuscitated endotoxic shock. In six pentobarbital-anesthetized dogs, shock was induced by Escherichia coli endotoxin infusion (1 mg/kg) and was treated with saline infusion to maintain mean arterial pressure > 80 mmHg. Blood gases and strong ions were measured during control conditions and at 15, 45, 90, and 180 min after endotoxin infusion. ⋯ Although serum Na+ did not change, serum Cl-increased (127.7+/-5.1 mmol/L vs. 137.0+/-6.1 mmol/L; p=.016). We conclude that saline resuscitation alone accounts for more than one-third of the acidosis seen in this canine model of acute endotoxemia, whereas lactate accounts for less than 10%. A large amount of the acid load can be attributed to differential Na+ and Cl- shifts from extravascular to vascular spaces.