Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse

Abstract

The release of cytokines following administration of endotoxin and the contribution of nitric oxide (NO) to the subsequent haemodynamic profile were investigated in the conscious mouse. Administration of endotoxin (E. Coli, 026:B6, 12.5 mg kg−1, i.v.) elevated the concentration of tumour necrosis factor‐α (TNF‐α) in the plasma within 0.5 h, reaching a maximum at 2 h and returning to control concentrations by 4 h. In addition, the concentration of interleukin‐6 (IL‐6) in the plasma was also elevated within 1 h, reaching a maximum at 3 h and remaining elevated throughout the 12 h of study. Endotoxin (12.5 mg kg−1, i.v.) induced the expression of a Ca2+‐independent (inducible) NO synthase in the mouse heart and elevated the concentrations of nitrite and nitrate in the plasma within 4 h, reaching a maximum at 12 h. This was accompanied by a progressive fall in blood pressure over the same period. The vasopressor effect of noradrenaline (0.5–4 μg kg−1 min−1, i.v.) administered as a continuous infusion was significantly attenuated 7 h after endotoxin (12.5 mg kg−1, i.v). The NO synthase inhibitor NG‐monomethyl‐L‐arginine HCl (L‐NMMA; 1–10 mg kg−1, i.v. bolus) reversed the fall in blood pressure when administered 7 h after endotoxin (12.5 mg kg−1, i.v.). In an attempt to maintain a constant blood concentration, L‐NMMA was administered as a continuous infusion (10 mg kg−1 h−1, i.v.), beginning 4 h after a lower dose of endotoxin (6 mg kg−1, i.v.). Such treatment prevented the fall in blood pressure and the elevation of nitrite and nitrate in the plasma throughout the 18 h of observation. The fall in blood pressure following endotoxin (3 mg kg−1, i.v.) was significantly reduced throughout the 18 h of observation in homozygous mutant mice lacking the inducible NO synthase. In summary, we have developed a model of endotoxin shock in the conscious mouse in which an overproduction of NO by the inducible NO synthase is associated with the haemodynamic disturbances. This model, which exhibits many of the characteristics of septic shock in man, will enable the study of the pathology of this condition in more detail and aid the investigation of potential therapeutic agents both as prophylactics and, more importantly, as treatments.

Hypertensive Response to Acute Stress Is Attenuated in Interleukin-6 Knockout Mice

“…Reports indicate that increased IL-6 occurs with endotoxin shock, cirrhosis, or septic shock and is associated with decreased blood pressure that may or may not be associated with stimulation of nitric oxide synthase. 22,23 However, there is new evidence that high blood pressure is associated with increasing levels of IL-6 in healthy men. 7 An additional study indicates that IL-6 causes vasoconstriction in the canine cerebral artery.…”

Elk-3 Is a Transcriptional Repressor of Nitric-oxide Synthase 2

“…Overproduction of NO, through LPS and proinflammatory cytokine activation of NOS2, acts as a key regulator of hypotension and end organ damage (4,5). Due to the detrimental consequences of an exaggerated response to infection, the immune system must be tightly controlled to prevent a massive systemic reaction leading to multiple organ failure and death.…”

“…This response to infection is mediated, in part, by macrophage activation and the release of proinflammatory cytokines (3). Among the mediators induced by these signal cascades, nitric oxide (NO) acts as a key regulator of hypotension and end organ damage (4,5). The production of nitric oxide from L-arginine is catalyzed by NO synthases (NOS) (6).…”

Mitochondrial dysfunction and HIF1α stabilization in inflammation

“…In addition, prolonged exposure to NO leads to non-competitive and persistent inhibition of complex I and other key respiratory enzymes by S-nitrosylation (Clementi et al, 1998;Orsi et al, 2000a;Beltran et al, 2000a); such persistent inhibition can be enhanced by hypoxia (Frost et al, 2005). These findings prompted us to suggest that tissue dysoxia, which is characteristic of septic shock, is due to overproduction of NO, resulting in a mitochondrial defect with the consequent decrease in the extraction of O 2 by tissues, leading ultimately to multiple organ failure and death (Rees et al, 1998;Orsi et al, 2000b). In recent years, evidence in favour of this hypothesis has been accumulating, including the demonstration of a significant mitochondrial defect in biopsies of skeletal muscle of individuals with sepsis (Brealey et al, 2002), the observation of an NO-dependent defect in complex I of biopsies obtained from animals with septic shock (Protti et al, 2007) and the preservation of mitochondrial activity in a septic shock model in inducible nitric oxide synthase (iNOS) knockout mice (Escames et al, 2007).…”