Johnson Robert A, Durante William, Craig Teresa, Peyton Kelly J, Myers John G, Stewart Ronald M, Johnson Fruzsina K
Division of Trauma and Emergency Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
J Trauma. 2010 Aug;69(2):384-91. doi: 10.1097/TA.0b013e3181e771a3.
Hemorrhagic shock causes hypoperfusion of peripheral tissues and promotes endothelial dysfunction, which may lead to further tissue injury. Trauma increases extrahepatic activity of arginase, an enzyme which competes for l-arginine with nitric oxide synthase, and plays a key role in the development of endothelial dysfunction during aging, hypertension, and diabetes. However, the role of arginase in hemorrhage-induced endothelial dysfunction has not been studied. This study tests the hypothesis that arginase inhibition improves endothelial function after hemorrhage.
Male Sprague-Dawley rats were implanted with indwelling arterial catheters for blood pressure measurements and blood removal. Awake animals were subjected to a 45% fixed volume controlled hemorrhage and blood pressure was monitored. Unbled rats served as controls. Skeletal muscle arterioles were isolated 24 hours after hemorrhage and cannulated in a pressure myograph system. To study endothelial function, arterioles were exposed to constant midpoint, but altered endpoint pressures, to establish graded levels of luminal flow and internal diameter was measured.
Hemorrhage lowered mean arterial pressure that spontaneously recovered to 78% and 88% of baseline in 2 hours and 20 hours, respectively. Vascular arginase II and blood glucose levels were elevated, whereas hemoglobin and insulin levels were decreased 24 hours after blood loss. In posthemorrhage arterioles, flow-induced dilation was abolished. Acute in vitro treatment with an inhibitor of arginase, N-hydroxy-nor-l-arginine, restored flow-induced dilation to unbled control levels. Similarly, the arginase and nitric oxide synthase substrate, l-arginine, but not the inactive isomer, d-arginine, restored flow-induced dilation.
These results indicate that arginase contributes to endothelial dysfunction in resistance vessels after significant hemorrhage.
失血性休克导致外周组织灌注不足，并促进内皮功能障碍，这可能会导致进一步的组织损伤。创伤会增加精氨酸酶的肝外活性，该酶与一氧化氮合酶竞争L-精氨酸，并在衰老、高血压和糖尿病期间内皮功能障碍的发展中起关键作用。然而，精氨酸酶在出血诱导的内皮功能障碍中的作用尚未得到研究。本研究检验了精氨酸酶抑制可改善出血后内皮功能的假设。
将雄性Sprague-Dawley大鼠植入留置动脉导管以测量血压和放血。清醒的动物接受45%固定容量的控制性出血，并监测血压。未放血的大鼠作为对照。出血24小时后分离骨骼肌小动脉，并在压力肌动描记系统中插管。为了研究内皮功能，将小动脉暴露于恒定的中点，但改变终点压力，以建立分级的管腔血流水平，并测量内径。
出血使平均动脉压降低，分别在2小时和20小时时自发恢复至基线的78%和88%。失血24小时后，血管精氨酸酶II和血糖水平升高，而血红蛋白和胰岛素水平降低。在出血后的小动脉中，血流诱导的舒张消失。用精氨酸酶抑制剂N-羟基-nor-L-精氨酸进行急性体外处理，可使血流诱导的舒张恢复至未放血对照水平。同样，精氨酸酶和一氧化氮合酶底物L-精氨酸，但不是无活性的异构体D-精氨酸，可恢复血流诱导的舒张。
这些结果表明，精氨酸酶在严重出血后导致阻力血管的内皮功能障碍。
