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


METHODS
University research laboratories.


METHODS
Sepsis was induced by cecal ligation and perforation in rats.


RESULTS
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.


CONCLUSIONS
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.
Nin
Nicolás
N
Department of Pathophysiology, Hospital de Clínicas, School of Medicine, Universidad de la República , Avenida Italia s/n, Piso 15, CP 11600 Montevideo, Uruguay.
Cassina
Adriana
A
Boggia
José
J
Alfonso
Evangelina
E
Botti
Horacio
H
Peluffo
Gonzalo
G
Trostchansky
Andrés
A
Batthyány
Carlos
C
Radi
Rafael
R
Rubbo
Homero
H
Hurtado
F Javier
FJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003964:Diaphragm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000627:therapeutic use*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption; D011659:Pulmonary Gas Exchange; D051381:Rats; D011921:Rats, Inbred WKY; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006146:Guanidines; D008665:Metalloporphyrins; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D019001:Nitric Oxide Synthase; C004479:pimagedine