Effects of hydrocortisone stress-dose therapy in septic shock (part I): influence on hemodynamic stability and plasma nitrite/nitrate levels

Background Recent evidence suggests that nitric oxide produced via the neuronal nitric oxide synthase is involved mainly in the early response to sepsis, whereas nitric oxide derived from the inducible nitric oxide synthase is responsible during the later phase. We hypothesized that early neuronal and delayed inducible nitric oxide synthase blockade attenuates multiple organ dysfunctions during sepsis. Methods Sheep were randomly allocated to sham-injured, nontreated animals (n = 6); injured (48 breaths of cotton smoke and instillation of Pseudomonas aeruginosa into the lungs), nontreated animals (n = 7); and injured animals treated with a neuronal nitric oxide synthase inhibitor from 1 to 12 h and an inducible nitric oxide synthase inhibitor from 12 to 24 h postinjury (n = 6). Results The injury induced arterial hypotension, vascular leakage, myocardial depression, and signs of renal and hepatic dysfunctions. The treatment significantly attenuated, but did not fully prevent, the decreases in mean arterial pressure and left ventricular stroke work index. Although the elevation of creatinine levels was partially prevented, the decreases in urine output and creatinine clearance were not affected. The injury-related increases in bilirubin levels, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated. Although plasma nitrite/nitrate levels were significantly increased versus baseline from 12-24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals. Conclusions The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.

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Contrasting effects of intervention with ETA and ETB receptor antagonists in hypertension induced by angiotensin II and high-salt dietThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-051 ◽

2010 ◽

Vol 88 (8) ◽

pp. 802-807 ◽

Cited By ~ 12

Author(s):

Erika I. Boesen ◽

Jennifer S. Pollock ◽

David M. Pollock

Keyword(s):

Angiotensin Ii ◽

Creatinine Clearance ◽

Nitrate Concentration ◽

Therapeutic Approaches ◽

Receptor Antagonists ◽

Induced Hypertension ◽

Etb Receptor ◽

Nitrite Nitrate ◽

Plasma Nitrite ◽

Selection Of

Endothelin (ET) receptor antagonists are antihypertensive and renoprotective in angiotensin II (AngII)-induced hypertension if administered when AngII infusion commences, but their effects on established hypertension are poorly understood. We therefore tested the effects of intervening with an ETA (ABT-627) or ETB (A-192621) receptor antagonist after establishing hypertension with AngII (65 ng/min s.c.) plus 8% NaCl diet (AngII–HS) in rats. Prior to administration of ABT-627, AngII–HS and AngII–HS plus ABT-627 groups displayed robust hypertension (mean arterial pressure (MAP), 170 ± 5 and 165 ± 5 mm Hg versus 110 ± 3 mm Hg in normal salt control rats at day 7, P < 0.05). Administering ABT-627 from day 8 of AngII–HS treatment prevented further rises in MAP (168 ± 5 and 191 ± 3 mm Hg at day 13 in AngII–HS plus ABT-627 and AngII–HS, P < 0.001), without blunting the significant increases in urinary protein (19-fold), albumin (25-fold), or MCP-1 excretion (6- to 8-fold) or the reduction in creatinine clearance. Administering A-192621 from day 8 mildly exacerbated AngII–HS induced hypertension (P < 0.05 for AngII–HS versus AngII–HS plus A-192621 on days 11 and 12 only) and reduced plasma nitrite/nitrate concentration (P < 0.05), without affecting proteinuria, albuminuria, or creatinine clearance. These results confirm the importance of ETA receptor signaling in maintaining AngII–HS hypertension and suggest that including ETB receptor blockade in therapeutic approaches to treating hypertension would be ineffective or even counterproductive.

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Hyperbaric oxygen treatment impacts oxidative stress markers in patients with necrotizing soft-tissue infection

Journal of Investigative Medicine ◽

10.1136/jim-2021-001837 ◽

2021 ◽

pp. jim-2021-001837

Author(s):

Morten Hedetoft ◽

Peter Østrup Jensen ◽

Claus Moser ◽

Julie Vinkel ◽

Ole Hyldegaard

Keyword(s):

Oxidative Stress ◽

Septic Shock ◽

Soft Tissue ◽

Hyperbaric Oxygen ◽

Soft Tissue Infection ◽

Tissue Infection ◽

Heme Oxygenase 1 ◽

Necrotizing Soft Tissue Infection ◽

Before And After ◽

Nitrite Nitrate

Necrotizing soft-tissue infection (NSTI) is a rare, severe, and fast-progressing bacterial infection associated with a high risk of developing sepsis or septic shock. Increasing evidence indicates that oxidative stress is crucial in the development and progression of sepsis, but its role in NSTI specifically has not been investigated. Some patients with NSTI receive hyperbaric oxygen (HBO2) treatment as the restoration of oxidative stress balance is considered an important mechanism of action, which HBO2 facilitates. However, a gap in knowledge exists regarding the effect of HBO2 treatment on oxidative stress in patients with NSTI. In the present observational study, we aimed to investigate HBO2 treatment effects on known markers of oxidative stress in patients with NSTI. We measured plasma myeloperoxidase (MPO), superoxide dismutase (SOD), heme oxygenase-1 (HO-1) and nitrite+nitrate in 80 patients with NSTI immediately before and after their first HBO2 treatment, and on the following day. We found that HBO2 treatment was associated with a significant increase in MPO and SOD by a median of 3.4 and 8.8 ng/mL, respectively. Moreover, we observed an HBO2 treatment-associated increase in HO-1 in patients presenting with septic shock (n=39) by a median of 301.3 pg/mL. All markers were significantly higher in patients presenting with septic shock compared to patients without shock, and all markers correlated with disease severity. High baseline SOD was associated with 90-day mortality. In conclusion, HBO2 treatment was associated with an increase in MPO and SOD in patients with NSTI, and oxidative stress was more pronounced in patients with septic shock.

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Exposure to Stress-Dose Steroids and Lethal Septic Shock After In-Hospital Cardiac Arrest: Individual Patient Data Reanalysis of Two Prior Randomized Clinical Trials that Evaluated the Vasopressin–Steroids–Epinephrine Combination Versus Epinephrine Alone

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-018-6811-0 ◽

2018 ◽

Vol 32 (4) ◽

pp. 339-351

Author(s):

Spyros D. Mentzelopoulos ◽

Iosifina Koliantzaki ◽

Marios Karvouniaris ◽

Charikleia Vrettou ◽

Nicolas Mongardon ◽

...

Keyword(s):

Septic Shock ◽

Clinical Trials ◽

Cardiac Arrest ◽

Randomized Clinical Trials ◽

Individual Patient Data ◽

Patient Data ◽

Hospital Cardiac Arrest ◽

Stress Dose

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Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

Blood ◽

10.1182/blood-2003-07-2240 ◽

2004 ◽

Vol 104 (1) ◽

pp. 43-50 ◽

Cited By ~ 52

Author(s):

Hagir B. Suliman ◽

Mervat Ali ◽

Claude A. Piantadosi

Keyword(s):

Superoxide Dismutase ◽

Regulatory Element ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Adaptation To Hypoxia ◽

Knock Out ◽

Superoxide Dismutase 3 ◽

Nitrite Nitrate ◽

Plasma Nitrite ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Abstract Extracellular superoxide dismutase (SOD3) is the primary extracellular enzymatic scavenger of superoxide (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(^{{\cdot}}\mathrm{O}_{2}^{-}\) \end{document}). SOD3's expression is highest in the kidney, but its distribution and biologic functions there are unknown. To investigate the function of renal SOD3, we colocalized it with erythropoietin (EPO) to proximal tubules using in situ hybridization and immunohistochemistry. We then exposed wild-type (Wt) and SOD3 knock-out (KO) mice to hypoxia and found a late hematocrit response in the KO strain. EPO mRNA expression was attenuated in KO mice during the first 6 hours of hypoxia preceded at 2 hours by less accumulation of nuclear hypoxia-inducible transcription factor 1 α (HIF-1α) protein. Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) and early significant increases in glutathione disulfide (GSSG)/glutathione (GSH), a marker of oxidative stress, compared with Wt mice. Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicating peroxynitrite formation, increased later in hypoxia, and renal endothelial nitric oxide synthase protein induction was similar in both strains. These data show that hypoxic activation of HIF-1α and its target gene EPO in mouse kidney is regulated closely by the oxidant/antioxidant equilibrium involving SOD3, thus identifying renal SOD3 as a regulatory element in the body's innate adaptation to hypoxia.

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