Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition

• Published in: Intensive care medicine 2004-12, Vol.30 (12), p.2271-2278
• Main Authors: NIN, Nicolas, CASSINA, Adriana, HURTADO, F. Javier, BOGGIA, José, ALFONSO, Evangelina, BOTTI, Horacio, PELUFFO, Gonzalo, TROSTCHANSKY, Andrés, BATTHYANY, Carlos, RADI, Rafael, RUBBO, Homero
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antioxidants; Biological and medical sciences; Blood Pressure - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Diaphragm - drug effects; Emergency and intensive care: infection, septic shock; Enzyme Inhibitors - therapeutic use; Guanidines - therapeutic use; Heart Rate - drug effects; Intensive care medicine; Laparotomy; Male; Medical sciences; Metalloporphyrins - therapeutic use; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Muscle Contraction - drug effects; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxygen Consumption; Pharmacology. Drug treatments; Plasma; Pulmonary Gas Exchange; Rats; Rats, Inbred WKY; Respiration; Respiratory failure; Sepsis; Sepsis - drug therapy; Sepsis - metabolism
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-004-2427-x

Decreased diaphragmatic contractility and organ failure observed during sepsis is mediated by an overproduction of nitric oxide ((.)NO)-derived species, mitochondria being a major target of oxidative and nitrative stress. We tested the potential protective effects of (a) a novel synthetic antioxidant, the manganese(III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP(5+)) and (b) the inducible (.)NO synthase inhibitor aminoguanidine (AG) on a rat model of sepsis. University research laboratories. Sepsis was induced by cecal ligation and perforation in rats. Systemic hemodynamics, pulmonary gas exchange, in vitro diaphragmatic function and mitochondrial respiration were evaluated. Moreover, plasma and mitochondrial oxidative and nitrative stress parameters were investigated. Sepsis determined diaphragmatic dysfunction and a significant decrease in mitochondrial coupling and respiration. Oxidative stress was evidenced by decreased plasma antioxidants and increased lipid oxidation. Tyrosine nitration was increased in the plasma and mitochondria of the septic animals. These alterations were ameliorated or prevented by either MnTE-2-PyP(5+) or AG. Our results demonstrate that overproduction of (.)NO and (.)NO-derived reactive species play a critical role in mitochondrial impairment and diaphragmatic function during sepsis. More importantly, AG but mainly the novel metalloporphyrin MnTE-2-PyP(5+) were able to ameliorate diaphragmatic and mitochondrial dysfunction and could contribute to preventing organ failure during severe sepsis.