Prevention of Multiple Organ Failure

Deitch, Edwin A.; Goodman, Elliot R.

doi:10.1016/s0039-6109(05)70088-8

Cited by 67 publications

(37 citation statements)

References 56 publications

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“…However, iNOS-derived NO synthesis does not appear to be of major hemodynamic significance for intrahepatic vascular resistance. [49][50][51] The 1998 Nobel Prize in Medicine honored the demonstration that NO relaxes vascular smooth muscle through the activation of cGMP. Regulating cGMP-production seemed to be the major role for NO.…”

Section: Atherosclerosis and Endothelial Dysfunction In The Intrahepamentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002

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C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

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Section: Atherosclerosis and Endothelial Dysfunction In The Intrahepamentioning

confidence: 99%

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

2002

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“…Bacterial translocation (BT) is the passage of viable intestinal bacteria and endotoxins through the intestine wall for the mesenteric lymphatic nodules, to other organs and systemic circulation [1][2][3][4] . This phenomenon is associated with bacteremia and septicemia, renal failure and pulmonary dysfunction, which can lead to multiple organ failure, and occasionally death.…”

Section: Introductionmentioning

confidence: 99%

Bacterial translocation in rats nonfunctioning diverted distal colon

Júnior

Brandt²,

Medeiros

et al. 2007

Acta Cir. Bras.

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Purpose:To investigate whether the alterations of the diverted colon segment mucosa, evidenced in fecal colitis, would be able to alter Bacterial Translocation (BT). Methods: Sixty-two Wistar male rats ranging from 220 to 320 grams of weight, were divided in two groups: A (Colostomy) and B (Control), with 31 animals each one. In group A, all animals underwent end colostomy, one stoma, in ascending colon; and in the 70 th POD was injected in five rats, by rectal routediverted segment -2ml of a 0.9% saline solution in animals (A1 subgroup); in eight it was inoculated, by rectal route, 2ml of a solution containing Escherichia coli ATCC 25922 (American Type Culture Collection), in a concentration of 10 8 Colony Forming Unit for milliliters (CFU/ml) -A2 Subgroup; in ten animals the same solution of E. coli was inoculated, in a concentration of 10 11 CFU/ml (A3 Subgroup); and in eight it was collected part of the mucus found in the diverted distal colonic segment for neutral sugars and total proteins dosage (A4 subgroup). The animals from the group B underwent the same procedures of group A, but with differences in the colostomy confection. In rats from subgroups A1, A2, A3, B1, B2, and B3 2ml of blood were aspirated from the heart, and fragments from mesenteric lymphatic nodule, liver, spleen, lung and kidney taken for microbiological analysis, after their death. This analysis consisted of evidencing the presence of E. coli ATCC 25922 CFU. Mann-Whitney and ANOVA Tests were applied as analytic techniques for association of variables. Results: The occurrence of BT was evidenced only in those animals in which inoculated concentration of E. coli ATCC 25922, reached levels of 10 11 CFU/ml, i.e. in Subgroups A3 and B3, although, being significantly greater (80%) in those animals without colostomy (subgroup B3) when compared to the ones with colostomy (20%) from the subgroup A3 (P <0.05). Lung, liver and mesenteric lymphatic nodules were the tissues with larger percentile of bacterial recovery, so much in subgroup A3, as in B3. Blood culture was considered positive in 60% of the animals from subgroup B3 and in 10% of those from subgroup A3 (p <0.05). There was greater concentration of neutral sugars, in subgroup A4 -mean 27.3mg/ml -, than in subgroup B4 -mean 8.4mg/ml -(P <0.05). Conclusion: The modifications in the architecture of intestinal mucosa in colitis following fecal diversion can cause alterations in the intestinal barrier, but it does not necessarily lead to an increased frequency of BT. Key words: Bacterial Translocation. Colitis. Rats, Wistar. RESUMO Objetivo: Investigar se as alterações do cólon desfuncionalizado, evidenciadas na colite de derivação fecal, seriam capazes de permitir Translocação Bacteriana (TB), ou se a mucosa intestinal atrofiada permitiria a passagem de bactérias para órgãos à distância. Métodos: Foram utilizados 62 ratos Wistar, machos, pesando entre 220 e 320 gramas, divididos em dois grupos: A (Colostomia) e B (Controle), contendo cada um 31 animais. No grupo A, os animais foram ...

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“…Septic shock is a refractory disorder which can result in morbidity despite therapeutic interventions (1,6,9,20). It is thought that overproduction of nitric oxide (NO) by NO synthase (NOS) contributes to circulatory disturbance, tissue damage, and refractory hypotension which often occur in patients with septic shock and which seriously affect the prognosis of these patients (10).…”

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confidence: 99%

Comparison of Effects of Nitric Oxide Synthase (NOS) Inhibitors on Plasma Nitrite/Nitrate Levels and Tissue NOS Activity in Septic Organs

Hayashi

Abe

Murai

et al. 2005

Microbiology and Immunology

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An excessive production of nitric oxide (NO) by NO synthase (NOS) is considered to contribute to circulatory disturbance, tissue damage, and refractory hypotention, which are often observed in septic disorders. It is anticipated that a selective inducible NOS (iNOS) inhibitor with excellent pharmacokinetics may be potentially effective as a novel and potent therapeutic intervention in sepsis. We examined whether or not a selective iNOS inhibitor shows iNOS selectivity at the tissue level, when administered systemically. The effects of four NOS inhibitors on plasma nitrite/nitrate (NOx) and tissue NOS levels were compared in major organs (lungs, liver, heart, kidneys, and brain) 6 hr after the injection of E. coli lipopolysaccharide (LPS) into male Wistar-King rats. The rats treated with the three iNOS inhibitors (N-(3-(aminomethyl)benzyl)acetamidine (1400W), (1S, 5S, 6R, 7R)-2-aza-7-chloro-3-imino-5-methylbicyclo [4.1.0] heptane hydrochloride (ONO-1714), and aminoguanidine) administered 1 hr after LPS injection, showed dose-dependent decreases in plasma NOx levels and NOS activity in the lungs. The non-selective NOS inhibitor (N G-methyl-L-arginine (L-NMMA)) had an effect only at the maximum dose. The differences in in vitro iNOS selectivity among these drugs did not correlate with iNOS selectivity at the tissue level. The relationship between plasma NOx levels and NOS activity in the lungs showed a linear relationship with or without the NOS inhibitors. In conclusion, the iNOS selectivity of these drugs does not seem to differ at the tissue level. Plasma NOx levels may be a useful indicator of lung NOS activity.

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Prevention of Multiple Organ Failure

Cited by 67 publications

References 56 publications

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

Bacterial translocation in rats nonfunctioning diverted distal colon

Comparison of Effects of Nitric Oxide Synthase (NOS) Inhibitors on Plasma Nitrite/Nitrate Levels and Tissue NOS Activity in Septic Organs

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