Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock

A major feature of septic shock is the development of a vascular crisis cha racterized by nonresponsiveness to sympathetic vasoconstrictor agents and t he subsequent irreversible fall in blood pressure. In addition, sepsis, lik e other inflammatory conditions, results in a large increase in the product ion of free radicals, including superoxide anions (O-2(radical anion)) with in the body. Here we show that O-2(radical anion) reads with catecholamines deactivating them in vitro. Moreover, this deactivation would appear to ac count for the hyporeactivity to exogenous catecholamines observed in sepsis , because administration of a superoxide dismutase (SOD) mimetic to a rat m odel of septic shock to remove excess O-2(radical anion) restored the vasop ressor responses to norepinephrine. This treatment with the SOD mimetic als o reversed the hypotension in these animals; suggesting that deactivation o f endogenous norepinephrine by O-2(radical anion) contributes significantly to this aspect of the vascular crisis. Indeed, the plasma concentrations o f both norepinephrine and epinephrine in septic rats treated with the SOD m imetic were significantly higher than in untreated rats. Interestingly. the plasma concentrations for norepinephrine and epinephrine were inversely re lated to the plasma concentrations of adrenochromes, the product of the aut oxidation of catecholamines initiated by O-2(radical anion). We propose, th erefore, that the use of a SOD mimetic represents a new paradigm for the tr eatment of septic: shock. By removing O-2(radical anion), exogenous and end ogenous catecholamines are protected from autoxidation. As a result, both h yporeactivity and hypotension are reversed, generation of potentially toxic adrenochromes is reduced, and survival rate is improved.