Christopher T A, Lopez B L, Ma X L, Feuerstein G Z, Ruffolo R R, Yue T L
Division of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5004, USA.
Br J Pharmacol. 1998 Jan;123(2):292-8. doi: 10.1038/sj.bjp.0701598.
1 Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new beta-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury. 2 Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg(-1) and 1.0 mg kg(-1), SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation. 3 Administration of 1 mg kg(-1) carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg(-1) carvedilol had no protective effects on post-ischaemic tissue injury. 4 Previous studies have shown that SB 211475 has virtually no beta-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.
活性氧已被证明在缺血后组织损伤中起关键作用。本实验旨在评估新型β-肾上腺素能受体拮抗剂卡维地洛的羟基化代谢产物SB 211475对大鼠内脏缺血（SI，60分钟）及再灌注（R）诱导的休克和组织损伤的影响。
在再灌注前2分钟给予SB 211475可剂量依赖性地减轻SI/R损伤。在0.5 mg·kg⁻¹和1.0 mg·kg⁻¹剂量下，SB 211475发挥了显著的抗休克和内皮保护作用，表现为生存时间延长、生存率提高、组织髓过氧化物酶活性和血细胞比容的升高减弱，以及内皮依赖性血管舒张得以保留。
给予1 mg·kg⁻¹卡维地洛可减轻休克诱导的组织损伤和内皮功能障碍。然而，给予0.5 mg·kg⁻¹卡维地洛对缺血后组织损伤没有保护作用。
先前的研究表明，SB 211475几乎没有β-阻断活性，但具有比卡维地洛更强的抗氧化活性。在本研究中，SB 211475发挥了比母体化合物更强的保护作用，表明卡维地洛的这种代谢产物在预防缺血后组织损伤方面优于卡维地洛。
