N-Allylsecoboldine as a novel agent prevents acute renal failure during endotoxemia

Blockades of cytokine and oxygen radicals release are considered to be beneficial in reducing multiple organ injury and increasing the survival rate in sepsis/septic shock. Thus, we examined the protective efficacy of N-allylsecoboldine, a secoaporphine derivative with antioxidant and alpha(1)-adrenoceptor blocking activities, in rats treated with endotoxin (E. coli lipopolysaccharide, LPS). Pretreatment of LPS-treated rats with N-allylsecoboldine significantly attenuated the late-phase hypotension, hypoglycemia and incremental plasma tumor necrosis factor (TNF)-alpha. Overproduction of plasma nitrate in endotoxemia was not changed but the continuous decrease of urinary nitrate appeared to be partially ameliorated by N-allylsecoboldine. However, N-allylsecoboldinc inhibited the inducible nitric oxide synthase (NOS) protein expression in the renal cortex of endotoxemic rats. N-allylsecoboldine also improved the endotoxemia-induced organ injury as demonstrated from the conspicuous recovery of marker enzymes in the LPS-treated rats. Endotoxemia was associated with renal dysfunctions as indicated by decreases in renal blood flow, urinary potassium excretion, and renal nitrate clearance. However, pretreatment with N-allylsecoboldine showed significant alleviation of these renal dysfunctions. In addition, a lower dose of N-allylsecoboldine ameliorated the mortality of LPS-treated mice. This study demonstrates N-allylsecoboldine's ability to avail against acute renal failure and increase survival rate during endotoxemia. These beneficial effects maybe attributed to the inhibition of NOS expression, TNF-alpha production, and free radical scavenging activities. However, the role of alpha(1)-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear. (c) 2006 Elsevier B.V. All rights reserved.