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 characterized by nonresponsiveness to sympathetic vasoconstrictor agents and the subsequent irreversible fall in blood pressure. In addition, sepsis, like other inflammatory conditions, results in a large increase in the production of free radicals, including superoxide anions (O(2)) within the body. Here we show that O(2) reacts with catecholamines deactivating them in vitro. Moreover, this deactivation would appear to account for the hyporeactivity to exogenous catecholamines observed in sepsis, because administration of a superoxide dismutase (SOD) mimetic to a rat model of septic shock to remove excess O(2) restored the vasopressor responses to norepinephrine. This treatment with the SOD mimetic also reversed the hypotension in these animals; suggesting that deactivation of endogenous norepinephrine by O(2) contributes significantly to this aspect of the vascular crisis. Indeed, the plasma concentrations of both norepinephrine and epinephrine in septic rats treated with the SOD mimetic were significantly higher than in untreated rats. Interestingly, the plasma concentrations for norepinephrine and epinephrine were inversely related to the plasma concentrations of adrenochromes, the product of the autoxidation of catecholamines initiated by O(2). We propose, therefore, that the use of a SOD mimetic represents a new paradigm for the treatment of septic shock. By removing O(2), exogenous and endogenous catecholamines are protected from autoxidation. As a result, both hyporeactivity and hypotension are reversed, generation of potentially toxic adrenochromes is reduced, and survival rate is improved.
Macarthur
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Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, MO 63104, USA. macarthu@slu.edu
Westfall
T C
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Riley
D P
DP
Misko
T P
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Salvemini
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D000323:Adrenochrome / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D007022:Hypotension / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008345:Manganese; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
D002395:Catecholamines; D008070:Lipopolysaccharides; D009942:Organometallic Compounds; D014662:Vasoconstrictor Agents; D013481:Superoxides; C121876:imisopasem manganese; D008345:Manganese; D000323:Adrenochrome; D013482:Superoxide Dismutase; D009638:Norepinephrine; D004837:Epinephrine