Nitric Oxide Synthase Inhibition in Sepsis? Lessons Learned from Large-Animal Studies (original) (raw)
Related papers
Hemodynamic and Cardiovascular Effects of Nitric Oxide Modulation in the Therapy of Septic Shock
Pharmacotherapy, 2000
Nitric oxide synthase (NOS) of the inducible subtype (iNOS) plays a pivotal role in vasodilation associated with sepsis. Various biochemical pathways are involved, revealing targets for inhibiting the consequence of iNOS activation. Interactions of transcription factors, inducers, cofactors, and regulators of iNOS are important in understanding the development of iNOS inhibitors. Inhibition through L-arginine analogs, depletion of arginine, inhibition of cofactors, modulating gene transcription, and scavenging nitric oxide have been studied. Human studies were conducted only with nonselective L-arginine analogs. Reduction of mortality from sepsis was not reported. It is anticipated that iNOS-specific compounds will be clinically useful. The focus of future human trials will be on these agents. Although ideal therapy for treating vasodilation from sepsis is not available, research into the pathophysiology of NOS in sepsis clarified the complexities surrounding this therapeutic dilemma. NOS = nitric oxide synthase; nNOS = neuronal NOS; iNOS = inducible NOS; eNOS = endothelial NOS; NMDA = N-methyl-D-aspartate; ADP = adenosine diphosphate.
Nitric oxide production in critically ill patients
Archives of Disease in Childhood, 1996
Objective-To measure serum nitrite and nitrate levels in critically ill children as indicators of endogenous nitric oxide (NO) production. Hypothesis-Endogenous NO production is increased in children with conditions characterised by immune stimulation. Design-Prospective descriptive study in a multidisciplinary paediatric intensive care unit. Patients-137 consecutive critically ill children with a variety of clinical conditions. Interventions-Using a rapid microtitre plate technique, daily serum nitrite and nitrate levels were measured from serum samples that remained in the clinical laboratory after daily routine phlebotomy. Clinical and laboratory information was also gathered daily for each patient. Results-The maximum serum nitrite plus nitrate levels (pM) reached by children with infection (41.8 (SD 18.1)), sepsis syndrome (85.1 (39.9)), shock without sepsis (36.4 (19.1)), transplantation alone (61.0 (43.4)), transplantation with sepsis (200.7 (150.5)), or rejection (161.7 (70.4)), were higher than in controls (18.1 (9.3)). In the absence of exogenous NO donors, levels greater than 80 FM were reached only in children with the sepsis syndrome, organ transplantation, or acute rejection. Conclusions-Increased endogenous NO production occurs in children with clinical conditions associated with immune stimulation. Further investigation is warranted to determine the value of this simple and rapid test as a clinically useful diagnostic tool and therapeutic monitor in the evaluation of children at risk for the sepsis syndrome or acute allograft rejection. (Arch Dis Child 1996;74:482-489)
In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis
The American Journal of Clinical Nutrition, 2006
Background: Arginine is important in the response to infections and is a precursor for the synthesis of the vasodilator nitric oxide (NO). Low plasma arginine is correlated with a worse prognosis in patients with sepsis, and increased NO has been implicated in the hypotension of sepsis. Data on in vivo arginine and NO kinetics are lacking in hypotensive septic adults. Objective: We aimed to measure in vivo arginine production and the intravascular NO synthesis rate in hypotensive septic patients. Design: Arginine flux and the fractional and absolute synthesis rates of plasma NO were measured in fasted healthy (n ҃ 10) and hypotensive septic (n ҃ 6) adults by using a 6-h constant infusion of [ 15 N 2-guanidino]arginine. Urinary excretion of the NO metabolites nitrite and nitrate (NOx) and plasma concentrations of NOx, arginine, and creatinine were also measured. Results: All patients had hyperdynamic septic shock and impaired renal function. Compared with the control subjects, the patients had slower arginine flux (99 Ȁ 8 compared with 50 Ȁ 7 mol • kg Ҁ1 • h Ҁ1 ; P 0.01), lower plasma arginine concentrations (75 Ȁ 8 compared with 40 Ȁ 11 mol/L; P 0.01), higher plasma NOx concentrations (30 Ȁ 4 compared with 65 Ȁ 1.8 mol/L), and a slower fractional synthesis rate of NOx. There was no significant difference in the absolute synthesis rate of NOx between groups. In patients with sepsis, the plasma NOx concentration correlated with the glomerular filtration rate and plasma creatinine but not with mean arterial pressure. Conclusions: Patients with septic shock have a shortage in the availability of arginine associated with a slower production. Impaired renal excretion of NOx is a contributor to the high plasma NOx in these patients.
Nitric Oxide and Vascular Reactivity in Sepsis
Shock, 2008
Sepsis and septic shock are major causes of morbidity and mortality in critically ill patients. Sepsis and septic shock induce a profound fall in the peripheral vascular tone. NO has been implicated as a key player in vascular changes of sepsis and septic shock. In this brief review, two points are focused in greater detail: first, the involvement of guanylate cyclase and potassium channels in NO vascular effects in sepsis; second, the role played by NO and its two effectors in the long-lasting modifications of vascular reactivity in sepsis. Some recent developments in the area are reviewed.
Markers of nitric oxide are associated with sepsis severity: an observational study
Critical Care
Background: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity. Method: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression. Results: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) μmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) μmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) μmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) μmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA. Conclusions: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.
Functional Inhibition of Constitutive Nitric Oxide Synthase in a Rat Model of Sepsis
American Journal of Respiratory and Critical Care Medicine, 2002
Induction of inducible nitric oxide synthase (iNOS) expression is likely important in the pathogenesis of sepsis. However, the sepsis-mediated induction of iNOS is associated with a decrease in constitutive NO synthase (cNOS) activity (which is reversible following acute but not chronic sepsis). Whether this decreased cNOS activity is due to functional inhibition of cNOS by the high concentrations of NO produced by iNOS or to downregulation of cNOS expression is not clear. Thus, we tested the hypothesis that sepsis produces a reversible iNOS/NO-mediated inhibition of cNOS activity. Using a rat cecal ligation and perforation (CLP) model of sepsis, we examined the time course of the changes in iNOS and cNOS activities in lung and thoracic aortae. Reversibility of the sepsis-induced decrease in cNOS activity was assessed in vitro by enzyme activity determination following selective inhibition of iNOS. iNOS and endothelial cNOS protein concentrations were determined by Western blotting. In all septic tissues, cNOS activity was depressed at 6, 12, 24, and 48 hours post-CLP. Inhibition of the increased iNOS activity with aminoguanidine, in vitro , partially restored cNOS activity following acute (6-12 hours) but not chronic sepsis (24-48 hours post-CLP). Consistent with the irreversible depression of cNOS activities in tissues following chronic sepsis, endothelial NOS protein concentrations declined progressively during the time course of sepsis. We have demonstrated the restoration of cNOS activity following in vitro inhibition of iNOS, early, and the downregulation of endothelial NOS, later, in a rat CLP model of sepsis. This suggests that further study is required before iNOSselective inhibition can be considered in human sepsis.
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
American Journal of Surgery, 1995
Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from l-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule.