A 37-year-old man with multiple somatic complaints

Catecholamines and volume repletion are currently used for the treatment of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) seems to be related to the hypotension and tissue damage of endotoxin shock. Thus, treatment with NO synthase inhibitors has been proposed. Using a rat model of septic shock we have studied the effects of noradrenaline or the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NMMA) on arterial pressure, tissue damage and NO production. Anaesthetized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cytosolic enzymes (transaminases and lactate dehydrogenase, markers of cell disruption) and nitrite plus nitrate (NO2-/NO3-, markers of NO production). A large proportion of these animals (40%) died before the end of the experiment. Co-treatment with noradrenaline resulted in temporary maintenance of arterial pressure followed by a decline, despite the dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO2-/NO3- or mortality compared with animals treated with lipopolysaccharide (LPS) alone. In contrast, administration of L-NMMA (10 mg kg-1) to septic animals prevented the fall in blood pressure and death caused by endotoxin. This treatment markedly diminished cell disruption, as measured by the plasma levels of necrosis enzymes, and partially, but significantly, reduced the production of NO as assessed by plasma NO2-/NO3-. We conclude that tissue damage in septic shock is related to the overproduction of NO and not exclusively to the hypotension that follows this increased production. Thus, maintenance of blood pressure with catecholamines fails to improve cellular damage. Instead, partial inhibition of NO generation is sufficient to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.