Christopher T A, Ma X L, Gauthier T W, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Am J Physiol. 1994 Mar;266(3 Pt 2):H867-73. doi: 10.1152/ajpheart.1994.266.3.H867.
We studied the effects of CP-0127, a novel bradykinin receptor antagonist, in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma-free amino-nitrogen (8.6 +/- 0.97 vs. 2.3 +/- 0.15 U/ml in control rats) and intestinal myeloperoxidase (MPO) activity (2.7 +/- 0.33 vs. 0.08 +/- 0.03 U/100 mg control rats, intestinal tissue), and a survival time of only 110 +/- 9 min. Moreover, superior mesenteric artery (SMA) rings isolated from rats subjected to traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine (ACh) significantly less than rings isolated from control rats (21 +/- 4 vs. 92 +/- 4%, P < 0.001). Administration of CP-0127 at a dose of 10 mg/kg subcutaneously completely blocked the hypotensive response to 2.5 micrograms/kg bradykinin injected intravenously in sham traumatic shock rats. CP-0127 given immediately posttrauma prolonged survival time to 219 +/- 27 min (P < 0.01) and attenuated the increases in plasma-free amino-nitrogen (3.7 +/- 0.41 U/ml, P < 0.01) and tissue MPO activities (1.2 +/- 0.71 U/100 mg intestinal tissue, P < 0.05). Furthermore, SMA endothelial function was significantly preserved (relaxation to ACh: 57 +/- 6%, P < 0.01) in CP-0127-treated traumatic shock rats. These results indicate that bradykinin plays an important role in tissue injury associated with traumatic shock and that CP-0127 affords significant protection, which may be achieved through inhibition of neutrophil-endothelial interaction and protection of vascular endothelial function.
我们研究了新型缓激肽受体拮抗剂CP - 0127在创伤性休克大鼠模型中的作用。戊巴比妥麻醉的大鼠经诺布尔 - 科利普鼓式创伤后进入休克状态，其特征为显著低血压、血浆游离氨基氮显著升高（对照组大鼠为2.3±0.15 U/ml，创伤组为8.6±0.97 U/ml）以及肠髓过氧化物酶（MPO）活性升高（对照组大鼠肠组织为0.08±0.03 U/100 mg，创伤组为2.7±0.33 U/100 mg），存活时间仅为110±9分钟。此外，从创伤性休克大鼠分离的肠系膜上动脉（SMA）环对内皮依赖性血管舒张剂乙酰胆碱（ACh）的舒张反应明显低于从对照大鼠分离的环（分别为21±4%和92±4%，P<0.001）。在假创伤性休克大鼠中，以10 mg/kg的剂量皮下注射CP - 0127可完全阻断静脉注射2.5微克/千克缓激肽引起的低血压反应。创伤后立即给予CP - 0127可将存活时间延长至219±27分钟（P<0.01），并减轻血浆游离氨基氮的升高（3.7±0.41 U/ml，P<0.01）和组织MPO活性（肠组织1.2±0.71 U/100 mg，P<0.05）。此外，在接受CP - 0127治疗的创伤性休克大鼠中，SMA内皮功能得到显著保留（对ACh的舒张反应：57±6%，P<0.01）。这些结果表明，缓激肽在与创伤性休克相关的组织损伤中起重要作用，且CP - 0127提供了显著的保护作用，这可能是通过抑制中性粒细胞与内皮细胞的相互作用以及保护血管内皮功能来实现的。
