Gut mucosal damage during endotoxic shock is due to mechanisms other than gut ischemia (original) (raw)
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Acta Anaesthesiologica Scandinavica, 1999
Background: Inhibition of nitric oxide synthase (NOS) has been claimed to be beneficial in septic shock. We investigated the overall and regional effects of a NOS-inhibitor on perfusion and metabolism during severe endotoxic shock. Methods: Nineteen anaesthetised pigs were catheterised and ultrasonic flow-probes were placed around the portal vein, the hepatic artery, and the superior mesenteric artery. Thirteen animals were given a 3-h infusion of endotoxin; in 6 of these an infusion of N G -nitro-L-arginine-methyl-ester (L-NAME) was started an hour after the start of endotoxin while 7 animals served as controls and received endotoxin only. Six animals were sham operated with no further intervention. Results: Endotoxin produced a hypodynamic shock with pulmonary hypertension. L-NAME did not increase arterial blood pressure, but deepened the fall in cardiac output and enhanced the increase in systemic and pulmonary vascular resistance. The infusion of endotoxin caused a decrease in flows in all regions. The addition of L-NAME induced a further decrease in the mesenteric artery flow only. L-NAME had no additional effect on hepatic artery flow ratio, while a transient decrease was seen in
Journal of Surgical Research, 2001
Inducible nitric oxide synthase (NOS 2) is thought to play a role in gut motility disorders that occur under proinflammatory conditions. Clinically, ileus occurs after sepsis and shock-induced gut ischemia/ reperfusion (I/R). The purpose of this study was to determine if NOS 2 mediates impaired intestinal transit in well-established models of both moderate and severe gut ischemia/reperfusion. At laparotomy, Sprague-Dawley rats had duodenal catheters placed. Small intestinal transit was determined by quantitating the percentage tracer (FITC-dextran) in 10 equal segments of intestine 30 min after catheter injection [expressed as the mean geometric center (MGC) of distribution]. Transit was assessed at 6 and 24 h after gut ischemia [45 or 75 min of superior mesenteric artery occlusion (SMAO) with sham laparotomy as control]. In a separate set of experiments, N 6-(iminoethyl)-L-lysine (L-NIL), a selective NOS 2 antagonist, was administered 1 h prior to laparotomy and transit was determined after 6 h as described above. Ileal NOS 2 expression was assessed by Western immunoblot and quantitative "real-time" RT-PCR. We observed that both 45 and 75 min of SMAO decreased intestinal transit at 6 h of reperfusion compared to sham. Ileal NOS 2 mRNA and protein were increased after 75, but not 45, min of SMAO. In addition, L-NIL improved transit after 75, but not 45, min of SMAO. We conclude that (1) NOS 2 is upregulated in the gut only after more severe ischemic insults, and (2) ileus is mediated, at least in part, by NOS 2 under these conditions.
Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
In hemorrhagic shock (HS), increased cytokine production contributes to tissue inflammation and injury through the recruitment of neutrophils [polymorphonuclear cells (PMN)]. HS stimulates the early expression of inducible nitric oxide synthase (iNOS) that modulates proinflammatory activation after hemorrhage. Experiments were performed to determine the contribution of iNOS to gut inflammation and dysmotility after HS. Rats subjected to HS (mean arterial pressure 40 mmHg for 2.5 h followed by resuscitation and death at 4 h) demonstrated histological signs of mucosal injury, impairment of intestinal smooth muscle contractility, extravasation of PMN, and increased gut mRNA levels of ICAM-1, IL-6, and granulocyte colony-stimulating factor (G-CSF). In addition, DNA binding activity of NF-κB and Stat3, an IL-6 signaling intermediate, was significantly increased. In shocked rats treated with the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine at the time of resuscitation, histological...
Small Intestinal Production of Nitric Oxide Is Decreased Following Resuscitated Hemorrhage
Journal of Surgical Research, 1998
Background. Small intestine microvascular vasoconstriction and hypoperfusion develop after resuscitation (RES) from hemorrhage (HEM), despite restoration of central hemodynamics. The responsible mechanisms are unclear. We hypothesized that the microvascular impairment following HEM/RES was due to decreased intestinal microvascular nitric oxide (NO) production.
Jejunal luminal nitric oxide during severe hypovolemia and sepsis in anesthetized pigs
Intensive Care Medicine, 2001
Multiple organ dysfunction syndrome (MODS) is associated with high mortality , and its obscure pathophysiology has not as yet offered cause-related therapeutic alternatives. Data from several laboratories suggest that gastrointestinal hypoperfusion is a critical event leading to MODS [3, 5]. The present study was undertaken to elucidate the relationship between splanchnic hypoperfusion and jejunal mucosal nitric oxide production. The radical NO is a regulator of a multitude of gastrointestinal functions, including the mucosal barrier properties [6, 7]. For example, vascular administration of NO donors may preserve intestinal epithelial permeability [8] and microcirculation [9] during occlusive intestinal ischemia and hypovolemia. On the other hand, excessive formation of NO, as seen during inflammation and septic shock, may induce intestinal damage
Gastric nitric oxide synthase expression during endotoxemia: Implications in mucosal defense in rats
Gastroenterology, 2002
Background & Aims: This study was performed to examine expression of gastric nitric oxide synthase (NOS) isoforms during endotoxemia in rats and to assess their role(s) in gastric injury from bile and ethanol. Methods: Lipopolysaccharide (LPS) enhanced the expression and activity of inducible nitric oxide synthase in gastric mucosa in a dose-and time-dependent manner. Results: Endothelial nitric oxide synthase and neural nitric oxide synthase expression did not significantly change, but constitutive nitric oxide synthase activity decreased over time. LPS alone caused injury to the gastric mucosa and disrupted F-actin filaments in the same cells with enhanced immunostaining for inducible nitric oxide synthase. LPS also exacerbated gastric injury from the mild irritants 5 mmol/L acidified taurocholate and 20% ethanol as did local intra-arterial infusion of the nitric oxide donor S-nitroso-N-acetyl-penicillamine. The selective inducible nitric oxide synthase inhibitor aminoguanidine negated LPS-induced exacerbation of gastric injury from these irritants. The nonselective NOS inhibitor N G -nitro-L-arginine methyl ester augmented the deleterious effects of LPS, an effect reversed by L-arginine but not D-arginine. Aminoguanidine, but not N G -nitro-L-arginine methyl ester, negated LPS-induced accumulation of gastric luminal nitrates. Conclusions: These data suggest that increased inducible NOS activity and decreased constitutive nitric oxide synthase activity are primarily responsible for exacerbating gastric injury from luminal irritants during endotoxemia. Moreover, septic patients may be more susceptible to gastric injury from bile during gastrointestinal ileus.
Intestinal nitric oxide in the normal and endotoxemic pig
Shock (Augusta, Ga.), 2002
The gut is considered a central organ in the pathogenesis of sepsis and multiple organ failure, where several mediators, including endothelin (ET) and nitric oxide (NO), are involved. The aim of the current study was to characterize, by direct measurements, the intestinal NO production in the anesthetized pig during normal and endotoxemic conditions. In pigs subjected to endotoxin infusion, there was a progressive decrease in jejunal luminal NO levels, as well as portal venous blood flow and blood pressure. The ET- blocker 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide (bosentan) completely reversed the reduction in portal venous blood flow without affecting intestinal NO levels. In control pigs, the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester dose-dependently decreased intestinal NO levels and mesenteric blood flow--effects that were reversed by L-arginine. We conclude that intestinal NO is a product of muco...
Journal of Pharmacology and Experimental Therapeutics, 2009
Systemic inflammatory response syndrome, as a consequence of ischemia/reperfusion (I/R), negatively influences the function of the affected organs. The objective of this study was to assess the role of nitric oxide (NO) in remote intestinal inflammatory response elicited by hindlimb I/R. To this end, C57BL/6 (wild type; WT) and inducible nitric-oxide synthase (iNOS)-deficient mice were subjected to bilateral hindlimb ischemia (1 h) followed by 6 h of reperfusion. Some WT mice were injected with iNOS inhibitor N-[3-(aminomethyl)benzyl] acetamidine (1400W) (5 mg/kg s.c.) immediately before reperfusion, and proinflammatory response was assessed 6 h later. Hindlimb I/R resulted in dysfunction of the small intestine as assessed by the increase in permeability [blood-to-lumen clearance of Texas Red-dextran (molecular mass 3 kDa)] and an increase in the luminal levels of tumor necrosis factor (TNF)-␣ protein and nitrate/nitrite (NO 2 Ϫ /NO 3 Ϫ ). The above-mentioned changes were
Nitric oxide and endothelin relationship in intestinal ischemia/reperfusion injury (II
Prostaglandins Leukotrienes and Essential Fatty Acids, 2001
Gastrointestinal mucosal blood flow is dependent on a balanced release of vasoactive substances from endothelium. Nitric oxide (NO) may increase the flow by vasodilatation and/or antiaggregation whereas endothelin (ET) may decrease it by vasoconstriction and aggregation. NO and ET may have counterbalancing effects on each other in tissue damage. In order to test this hypothesis, in this study on rats, L-arginine to increase NO levels and NG-nitro-L-arginine methyl esther (L-NAME) to decrease NO levels have been used in an intestinal ischemia/ reperfusion (I/R) injury model and portal vein ET response was evaluated. Lipid peroxidation product measurements and chemiluminescence (CL) studies were also carried out in ileal tissue samples. Intestinal I/R injury caused an increase in portal venous ET levels with levels of 9.4_+0.5 fmol/ml in sham operation and 14.8_+1.6 fmol/ml in I/R group. ET level of L-NAME-sh group was lower than that of sham-operated group and also ET level of L-NAME-I/R group was lower than that of I/R group. This yielded the conclusion that inhibition of NO synthesis decreases portal venous ET levels in this model. Increased NO production by L-arginine caused increased ET levels in sham operated groups but this effect was not observed in I/R injury state. This study also showed that inhibition of NO synthesis has a protective role by reducing the reperfusion damage in this model. It is likely that NO and ET have a feedback effect on each other both under physiologic conditions and I/R injury.