Influence of specific endothelin-1 receptor blockers on hemodynamic parameters and antioxidant status of plasma in LPS-induced endotoxemia

Abstract

BackgroundThe potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of plasma oxidative stress seen in sepsis. The selective endothelin receptor blockers BQ123 andBQ788 were used to investigate the importance of selective endothelin receptor blockage in modulating oxidative stress during endotoxemia. MethodsThe study was performed on male Wistar rats (n=6 per group) divided into groups: (1) saline, (2) lipopolysaccharide (LPS) (15mg\\kg)-saline, (3) BQ123 (0.5mg\\kg)-LPS, (4) BQ123 (1mg\\kg)-LPS, (5) BQ788 (3mg\\kg)-LPS. The endothelin receptor type A (ETA-R) or type B (ETB-R) antagonist was injected intravenously 30min before LPS administration. Blood pressure was monitored and blood was taken before, 90min and 300min after saline or LPS administration. ResultsInjection of LPS alone resulted in a decrease in mean arterial pressure (MAP) (p<0.05), a decrease in ferric reducing ability of plasma (FRAP) value (p<0.01) and a marked increase in plasma tumor necrosis factor α (TNF-α) and thiobarbituric acid reactive substances (TBARS) (p<0.001, p<0.001, respectively). Administration of BQ123 before LPS administration deteriorated MAP in a dose dependent way. Moreover, BQ123 (1mg\\kg) decreased plasma level of TBARS and TNF-α (p<0.01 and p<0.05, respectively) and increased FRAP value (p<0.001). On the contrary, BQ788 prevented LPS-induced decrease in MAP (p<0.001) and led to a significant reduction in plasma TBARS concentration (p<0.01). ConclusionOur study showed that blockage of ETB-R during endotoxemia improved blood hemodynamics and decreased plasma lipid peroxidation. Blockage of ETA-R improved plasma antioxidant status and decreased lipid peroxidation and TNF-a production, but it deteriorated hemodynamic conditions.