n-allylsecoboldine and Acute-Kidney-Injury

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 alpha1-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-allylsecoboldine inhibited the inducible nitric oxide synthase (iNOS) 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 may be attributed to the inhibition of iNOS expression, TNF-alpha production, and free radical scavenging activities. However, the role of alpha1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear.

Topics: Acute Kidney Injury; Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Agonists; Animals; Aorta, Thoracic; Aporphines; Blood Flow Velocity; Blood Pressure; Dose-Response Relationship, Drug; Endotoxemia; Hypoglycemia; In Vitro Techniques; Kidney; Kidney Cortex; Lipopolysaccharides; Male; Nitrates; Nitric Oxide Synthase Type II; Norepinephrine; Phenylephrine; Rats; Rats, Wistar; Sepsis; Survival Rate; Tumor Necrosis Factor-alpha; Vasoconstriction; Vasoconstrictor Agents