Open AccessCPU0213, a novel endothelin receptor antagonist, ameliorates septic renal lesion by suppressing ET system and NF‐κB in rats 1
Author(s) -
HE Haibo,
DAI Dezai,
DAI Yin
Publication year - 2006
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2006.00373.x
Subject(s) - endothelin receptor , endocrinology , creatinine , medicine , nitric oxide , renal cortex , blood urea nitrogen , septic shock , kidney , endothelin receptor antagonist , endothelin 1 , receptor antagonist , renal function , tumor necrosis factor alpha , antagonist , receptor , sepsis
Aim: To examine whether a novel endothelin receptor antagonist, CPU0213, is effective in relieving the acute renal failure (ARF) of septic shock by suppressing the activated endothelin‐reactive oxygen species (ET‐ROS) pathway and nuclear factor kappa B (NF‐κB). Methods: The cecum was ligated and punctured in rats under anesthesia. CPU0213 (30 mg·kg −1 ·d −1 , bid, sc×3 d) was administered 8 h after surgical operation. Results: In the untreated septic shock group, the mean arterial pressure and survival rate were markedly decreased ( P <0.01), and heart rate, weight index of kidney, serum creatinine and blood urea nitrogen, 24 h urinary protein and creatinine were significantly increased ( P <0.01). The levels of ET‐1, total NO synthetase (tNOS), indusible nitric oxide synthetase (iNOS), nitric oxide (NO), and ROS in serum and the renal cortex were markedly increased ( P <0.01). The upregulation of the mRNA levels of preproET‐1, endothelin converting enzyme, ET A , ET B , iNOS, and tumor necrosis factor‐alpha in the renal cortex was significant ( P <0.01). The protein amount of activated NF‐κB was significantly increased ( P <0.01) in comparison with the sham operation group. All of these changes were significantly reversed after CPU0213 administration. Conclusion: Upregulation of the ET signaling pathway and NF‐κB play an important role in the ARF of septic shock. Amelioration of renal lesions was achieved by suppressing the ET A and ET B receptors in the renal cortex following CPU0213 medication.