Influence of Endothelin 1 Receptor Blockers and a Nitric Oxide Synthase Inhibitor on Reactive Oxygen Species Formation in Rat Lungs

Abstract

This study was designated to estimate protective role of ETA and ETB receptor antagonist against endothelin 1 (ET-1)-induced oxidative stress in lungs and determine whether these effects are mediated by nitric oxide (NO) synthase. Experiments were performed on Wistar rats divided into the following groups: I – saline (0.9 % NaCl); II – ET-1 (3 μg/kg b.w.), III – BQ123 (1 mg/kg b.w.) + ET-1 (3 μg/kg b.w.), IV – BQ788 (3 mg/kg b.w.) + ET-1 (3 μg/kg b.w.), V – N-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg b.w.) + ET-1 (3 μg/kg b.w.). ETA and ETB receptor antagonists or L-NAME were administered 30 min before ET-1 injection. The levels of the following substances were measured in the lungs homogenates: thiobarbituric acid reactive substances (TBARS), hydrogen peroxide (H2O2), reduced glutathione (GSH) and tumor necrosis factor-alpha (TNF-α). The results showed that ET-1 significantly increased TBARS, H2O2 (respectively: p<0.001, p<0.02) and TNF-α levels (p<0.02) and decreased the GSH level (p<0.01) vs. control group. On the other hand, prior administration of ETA receptor blocker (BQ123) significantly attenuated TBARS (p<0.01), H2O2 (p<0.02), TNF-α (p<0.02) and increased GSH (p<0.02) levels vs. ET-1. However, prior administration of ETB receptor blocker BQ788 did not cause significant changes in the: TBARS, H2O2 and TNF-α (p>0.05) levels, but significantly increased the GSH level and GSH/GSSG ratio (p<0.05). Administration of L-NAME significantly attenuated TBARS (p<0.001), H2O2 (p<0.05), TNF-α (p<0.01) and increased GSH (p<0.05) levels vs. ET-1. In conclusion, we demonstrated that ET-1 induced oxidative stress in the lungs is mediated by ETA receptors. ETA receptor blockage inhibited generation of free radicals and TNF-α and ameliorated antioxidant properties. Moreover, generation of reactive oxygen species is mediated by NOS in the lungs.