Beneficial effects of mercaptoethylguanidine, an inhibitor of the inducible isoform of nitric oxide synthase and a scavenger of peroxynitrite, in a porcine model of delayed hemorrhagic shock

Andrea Szabó, Paul Hake, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Objective: In rodent models, enhanced formation of nitric oxide and formation of peroxynitrite have been implicated in the pathogenesis of various forms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), an inducible nitric oxide synthase inhibitor and peroxynitrite scavenger, in a severe hemorrhagic shock model. Design: Randomized, placebo- controlled trial. Setting: Animal laboratory. Subjects: Twenty-one anesthetized immature Yorkshire pigs. Interventions: Mechanical ventilation, sternotomy, continuous cardiac output (pulmonary artery flowmetry), and systemic and intracardial pressure measurements were taken. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 hrs, which was followed by saline resuscitation (20 mL/kg). MEG was administered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusion). Measurements and Main Results: Hemodynamic variables, systemic and mixed venous blood gas tensions and oxygenation, arterial lactate concentration, myeloperoxidase activity, malondialdehyde content, and histologic injury in the lung and intestine were measured. Reduction of cardiac output to 40 mL/kg/min led to the following changes during hypovolemia: decreases in mean arterial blood pressure (to 30- 35 mm Hg), both atrial pressures, systemic oxygen consumption (by 35%), mixed venous saturation (by 65%), and lactic acidosis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and cardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil deposition, and severe histologic alterations in the lung and intestine. MEG significantly ameliorated the decrease in blood pressure and cardiac output during resuscitation, improved survival rate, reduced lipid peroxidation in the intestine, and ameliorated neutrophil accumulation in the lung and intestine. MEG prevented the reduction in oxygen consumption during resuscitation. Conclusions: When given during resuscitation, MEG exerted beneficial effects in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.

Original languageEnglish (US)
Pages (from-to)1343-1350
Number of pages8
JournalCritical Care Medicine
Volume27
Issue number7
DOIs
StatePublished - Jul 1999
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Hemorrhagic Shock
Nitric Oxide Synthase Type II
Resuscitation
Protein Isoforms
Swine
Cardiac Output
Intestines
Arterial Pressure
Oxygen Consumption
Lipid Peroxidation
Neutrophils
Hemodynamics
Blood Pressure
Lung
Lactic Acidosis
Hypovolemia
Atrial Pressure
Sternotomy
Rheology

Keywords

  • Cardiac output
  • Decompensation
  • Hemorrhagic shock
  • Histology
  • Malondialdehyde
  • Mercaptoethylguanidine
  • Myeloperoxidase
  • Peroxynitrite
  • Porcine
  • Survival

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

@article{c75aee9f44c74a7cbdcb60be6c39ae15,
title = "Beneficial effects of mercaptoethylguanidine, an inhibitor of the inducible isoform of nitric oxide synthase and a scavenger of peroxynitrite, in a porcine model of delayed hemorrhagic shock",
abstract = "Objective: In rodent models, enhanced formation of nitric oxide and formation of peroxynitrite have been implicated in the pathogenesis of various forms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), an inducible nitric oxide synthase inhibitor and peroxynitrite scavenger, in a severe hemorrhagic shock model. Design: Randomized, placebo- controlled trial. Setting: Animal laboratory. Subjects: Twenty-one anesthetized immature Yorkshire pigs. Interventions: Mechanical ventilation, sternotomy, continuous cardiac output (pulmonary artery flowmetry), and systemic and intracardial pressure measurements were taken. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 hrs, which was followed by saline resuscitation (20 mL/kg). MEG was administered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusion). Measurements and Main Results: Hemodynamic variables, systemic and mixed venous blood gas tensions and oxygenation, arterial lactate concentration, myeloperoxidase activity, malondialdehyde content, and histologic injury in the lung and intestine were measured. Reduction of cardiac output to 40 mL/kg/min led to the following changes during hypovolemia: decreases in mean arterial blood pressure (to 30- 35 mm Hg), both atrial pressures, systemic oxygen consumption (by 35{\%}), mixed venous saturation (by 65{\%}), and lactic acidosis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and cardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil deposition, and severe histologic alterations in the lung and intestine. MEG significantly ameliorated the decrease in blood pressure and cardiac output during resuscitation, improved survival rate, reduced lipid peroxidation in the intestine, and ameliorated neutrophil accumulation in the lung and intestine. MEG prevented the reduction in oxygen consumption during resuscitation. Conclusions: When given during resuscitation, MEG exerted beneficial effects in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.",
keywords = "Cardiac output, Decompensation, Hemorrhagic shock, Histology, Malondialdehyde, Mercaptoethylguanidine, Myeloperoxidase, Peroxynitrite, Porcine, Survival",
author = "Andrea Szab{\'o} and Paul Hake and Salzman, {Andrew L.} and Csaba Szabo",
year = "1999",
month = "7",
doi = "10.1097/00003246-199907000-00027",
language = "English (US)",
volume = "27",
pages = "1343--1350",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Beneficial effects of mercaptoethylguanidine, an inhibitor of the inducible isoform of nitric oxide synthase and a scavenger of peroxynitrite, in a porcine model of delayed hemorrhagic shock

AU - Szabó, Andrea

AU - Hake, Paul

AU - Salzman, Andrew L.

AU - Szabo, Csaba

PY - 1999/7

Y1 - 1999/7

N2 - Objective: In rodent models, enhanced formation of nitric oxide and formation of peroxynitrite have been implicated in the pathogenesis of various forms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), an inducible nitric oxide synthase inhibitor and peroxynitrite scavenger, in a severe hemorrhagic shock model. Design: Randomized, placebo- controlled trial. Setting: Animal laboratory. Subjects: Twenty-one anesthetized immature Yorkshire pigs. Interventions: Mechanical ventilation, sternotomy, continuous cardiac output (pulmonary artery flowmetry), and systemic and intracardial pressure measurements were taken. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 hrs, which was followed by saline resuscitation (20 mL/kg). MEG was administered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusion). Measurements and Main Results: Hemodynamic variables, systemic and mixed venous blood gas tensions and oxygenation, arterial lactate concentration, myeloperoxidase activity, malondialdehyde content, and histologic injury in the lung and intestine were measured. Reduction of cardiac output to 40 mL/kg/min led to the following changes during hypovolemia: decreases in mean arterial blood pressure (to 30- 35 mm Hg), both atrial pressures, systemic oxygen consumption (by 35%), mixed venous saturation (by 65%), and lactic acidosis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and cardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil deposition, and severe histologic alterations in the lung and intestine. MEG significantly ameliorated the decrease in blood pressure and cardiac output during resuscitation, improved survival rate, reduced lipid peroxidation in the intestine, and ameliorated neutrophil accumulation in the lung and intestine. MEG prevented the reduction in oxygen consumption during resuscitation. Conclusions: When given during resuscitation, MEG exerted beneficial effects in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.

AB - Objective: In rodent models, enhanced formation of nitric oxide and formation of peroxynitrite have been implicated in the pathogenesis of various forms of shock. Here we examined the effect of mercaptoethylguanidine (MEG), an inducible nitric oxide synthase inhibitor and peroxynitrite scavenger, in a severe hemorrhagic shock model. Design: Randomized, placebo- controlled trial. Setting: Animal laboratory. Subjects: Twenty-one anesthetized immature Yorkshire pigs. Interventions: Mechanical ventilation, sternotomy, continuous cardiac output (pulmonary artery flowmetry), and systemic and intracardial pressure measurements were taken. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 hrs, which was followed by saline resuscitation (20 mL/kg). MEG was administered in the resuscitation fluid (15 mg/kg bolus plus 15 mg/kg/hr infusion). Measurements and Main Results: Hemodynamic variables, systemic and mixed venous blood gas tensions and oxygenation, arterial lactate concentration, myeloperoxidase activity, malondialdehyde content, and histologic injury in the lung and intestine were measured. Reduction of cardiac output to 40 mL/kg/min led to the following changes during hypovolemia: decreases in mean arterial blood pressure (to 30- 35 mm Hg), both atrial pressures, systemic oxygen consumption (by 35%), mixed venous saturation (by 65%), and lactic acidosis (5.5-6.0 mM). Fluid replacement failed to restore blood pressure and cardiac output during resuscitation and was followed by gradual hemodynamic decompensation. Hemorrhagic shock induced lipid peroxidation, neutrophil deposition, and severe histologic alterations in the lung and intestine. MEG significantly ameliorated the decrease in blood pressure and cardiac output during resuscitation, improved survival rate, reduced lipid peroxidation in the intestine, and ameliorated neutrophil accumulation in the lung and intestine. MEG prevented the reduction in oxygen consumption during resuscitation. Conclusions: When given during resuscitation, MEG exerted beneficial effects in a porcine model of severe hemorrhagic shock. We propose that the mode of MEG's action is related to improved cardiac contractility.

KW - Cardiac output

KW - Decompensation

KW - Hemorrhagic shock

KW - Histology

KW - Malondialdehyde

KW - Mercaptoethylguanidine

KW - Myeloperoxidase

KW - Peroxynitrite

KW - Porcine

KW - Survival

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U2 - 10.1097/00003246-199907000-00027

DO - 10.1097/00003246-199907000-00027

M3 - Article

VL - 27

SP - 1343

EP - 1350

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 7

ER -