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 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.
Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei 100, Taiwan.
Chin-Wei
CW
Chiao
Shoei-Sheng
SS
Lee
Chin-Chen
CC
Wu
Ming-Jai
MJ
Su
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001060:Aporphines / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications* / Q000401:mortality; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009566:Nitrates / Q000097:blood / Q000652:urine; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D001060:Aporphines; D008070:Lipopolysaccharides; C090152:N-allylsecoboldine; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine