Chair of Experimental and Clinical Physiology, Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, PL 92-215 Łódź, Poland.
Pharmacol Rep. 2011;63(2):494-500. doi: 10.1016/s1734-1140(11)70516-3.
The aim of this study was to assess whether endothelin-A receptor (ET(A)-R) blocker, BQ123, influences lung edema, lipid peroxidation TBARS), hydrogen peroxide (H(2)O(2)), TNF-α concentration or the glutathione redox system in the lung homogenates obtained from LPS-induced endotoxic shock rats. The study was performed on male Wistar rats (n = 6 per group) divided into groups: (1) saline, (2) LPS (15 mg/kg)-saline, (3) BQ123 (0.5 mg/kg)-LPS, (4) BQ123 (1 mg/kg)-LPS. The ET(A)-R antagonist was injected intravenously 30 min before LPS administration. Five hours after saline or LPS administration, animals were sacrificed and lungs were isolated for indices of lung edema, oxidative stress and TNF-α concentration. Injection of LPS alone resulted in lung edema development and a marked increase in TNF-α (p < 0.02), TBARS (p < 0.02), and H(2)O(2) (p < 0.01) concentrations as well as a depletion of total glutathione (p < 0.01). Administration of BQ123 (1 mg/kg), before LPS challenge, led to a significant reduction in TNF-α and H(2)O(2) concentrations (p < 0.05) and elevation of both total glutathione and the GSH/GSSG ratio (p < 0.05). However, it did not prevent LPS-induced TBARS increase and lung edema formation. Interestingly, a lower dose of BQ123 was much more effective in decreasing H(2)O(2), TBARS, as well as TNF-α levels (p < 0.02, p < 0.05, p < 0.05, respectively). That dose was also effective in prevention of lung edema development (p < 0.01). Taken together, the obtained results indicate that BQ123 is highly effective in decreasing LPS-induced oxidative stress in lungs. Moreover, the dose of 0.5 mg/kg of the antagonist showed to be more effective in decreasing free radical generation and lung edema in endotoxemic rats.
本研究旨在评估内皮素 A 受体 (ET(A)-R) 拮抗剂 BQ123 是否会影响 LPS 诱导的内毒素休克大鼠肺组织中的肺水肿、脂质过氧化 (TBARS)、过氧化氢 (H(2)O(2))、TNF-α 浓度或谷胱甘肽氧化还原系统。该研究在雄性 Wistar 大鼠（每组 6 只）上进行，分为以下几组：(1) 生理盐水组，(2) LPS(15mg/kg)-生理盐水组，(3) BQ123(0.5mg/kg)-LPS 组，(4) BQ123(1mg/kg)-LPS 组。ET(A)-R 拮抗剂在 LPS 给药前 30 分钟静脉注射。在给予生理盐水或 LPS 后 5 小时，处死动物并分离肺组织，用于评估肺水肿、氧化应激和 TNF-α 浓度的指标。单独注射 LPS 会导致肺水肿的发展和 TNF-α（p < 0.02）、TBARS（p < 0.02）和 H(2)O(2)（p < 0.01）浓度的显著增加，以及总谷胱甘肽的消耗（p < 0.01）。在 LPS 攻击前给予 BQ123（1mg/kg）会导致 TNF-α 和 H(2)O(2)浓度的显著降低（p < 0.05），以及总谷胱甘肽和 GSH/GSSG 比值的升高（p < 0.05）。然而，它并没有阻止 LPS 诱导的 TBARS 增加和肺水肿的形成。有趣的是，较低剂量的 BQ123 更有效地降低了 H(2)O(2)、TBARS 和 TNF-α 水平（p < 0.02、p < 0.05、p < 0.05，分别）。该剂量也能有效预防肺水肿的发展（p < 0.01）。综上所述，研究结果表明 BQ123 能有效降低 LPS 诱导的肺部氧化应激。此外，拮抗剂 0.5mg/kg 的剂量在减少内毒素血症大鼠自由基生成和肺水肿方面更为有效。
