COMPARATIVE EFFECTS OF NITRIC-OXIDE SYNTHESIS INHIBITION AND CATECHOLAMINE TREATMENT IN A RAT MODEL OF ENDOTOXIN-SHOCK

Catecholamines and volume repletion are currently used for the treatme nt of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) se ems to be related to the hypotension and tissue damage of endotoxin sh ock. Thus, treatment with NO synthase inhibitors has been proposed. Us ing a rat model of septic shock we have studied the effects of noradre naline or the NO synthase inhibitor, NG-nitro-L-arginine methylester ( L-NMMA) on arterial pressure, tissue damage and NO production. Anaesth etized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cy tosolic enzymes (transaminases and lactate dehydrogenase, markers of c ell disruption) and nitrite plus nitrate (NO2-/NO3-, markers of NO pro duction). A large proportion of these animals (40%) died before the en d of the experiment. Co-treatment with noradrenaline resulted in tempo rary maintenance of arterial pressure followed by a decline, despite t he dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO2-/NO3- or mortality compared with animal s treated with lipopolysaccharide (LPS) alone. In contrast, administra tion 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 necros is enzymes, and partially, but significantly, reduced the production o f NO as assessed by plasma NO2-/NO3-. We conclude that tissue damage i n septic shock is related to the overproduction of NO and not exclusiv ely to the hypotension that follows this increased production. Thus, m aintenance of blood pressure with catecholamines fails to improve cell ular damage. Instead, partial inhibition of NO generation is sufficien t to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.