Acta Pharmacologica Sinica 2006 September; 27 (9): 1213-1221; doi: 10.1111/j.1745-7254.2006.00373.x

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-kB).

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-kB 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-kB 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.

Keywords: septic shock; acute renal failure; endothelin receptor antagonist; NF-kB; reactive oxygen species