Serebruany V L, Yurovsky V V, Gurbel P A
Sinai Center for Thrombosis Research, University of Maryland School of Medicine, Baltimore 21201, USA.
Life Sci. 1999;65(14):1503-13. doi: 10.1016/s0024-3205(99)00391-4.
NPC 15669, a member of the leumedins family, inhibits leukocyte adhesion to the endothelium by blockage of upregulation of a member of beta2 integrin family Mac-1 (CD11b/CD18). Inhibition of neutrophil-endothelial interactions may alter the course of myocardial reperfusion injury. However, the effects of NPC 15669 supplementation on the hemostatic profile during ischemia-reperfusion are unknown. The aim of the present study was to define changes in the certain hemostatic factors in the natural course of preconditioned myocardial infarction. Twelve consecutive Yorkshire swine underwent myocardial stunning (8 min. left anterior descending artery occlusion followed by 90 min. of reperfusion) and then preconditioned myocardial infarction (50 min. occlusion followed by 3 hours of reperfusion) experiments. NPC 15669 (10 mg/kg loading dose followed by constant infusion at 6 mg x kg(-1) x h(-1)) was administered in 6 animals; another 6 swine received saline and served as controls. Blood samples were obtained at baseline, twice during occlusion; and three times during reperfusion. The levels of antithrombin-III, Protein C, total Protein S, fibronectin, endothelin-1, as well as the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a), were determined. NPC 15669 treatment was associated with diminished endothelin-1, TxB2 levels and increased fibronectin, 6-keto-PGF1a, Protein C and total Protein S concentrations in the setting of preconditioned myocardial infarction. There were no changes in the plasma concentrations of antithrombin-III in NPC 15669 group when compared with controls. The increase in Protein C, total Protein S, and 6-keto-PGF1a (favoring antithrombosis), and decrease in endothelin-1 and TxB2 levels (favoring vasodilatation), following NPC 15669 may explain the reduction in infarct size previously reported with this agent.
NPC 15669是亮氨酸丰富重复序列跨膜蛋白家族的一员，它通过阻断β2整合素家族成员Mac-1（CD11b/CD18）的上调来抑制白细胞与内皮的黏附。抑制中性粒细胞与内皮的相互作用可能会改变心肌再灌注损伤的进程。然而，补充NPC 15669对缺血再灌注期间止血状况的影响尚不清楚。本研究的目的是确定预处理心肌梗死自然病程中某些止血因子的变化。连续12只约克夏猪接受心肌顿抑（左前降支动脉闭塞8分钟，随后再灌注90分钟），然后进行预处理心肌梗死（闭塞50分钟，随后再灌注3小时）实验。6只动物给予NPC 15669（负荷剂量10 mg/kg，随后以6 mg·kg⁻¹·h⁻¹持续输注）；另外6只猪接受生理盐水作为对照。在基线、闭塞期间两次以及再灌注期间三次采集血样。测定抗凝血酶III、蛋白C、总蛋白S、纤连蛋白、内皮素-1以及血栓素（TxB2）和前列环素（6-酮-前列腺素F1α）的稳定代谢产物的水平。在预处理心肌梗死的情况下，NPC 15669治疗与内皮素-1、TxB2水平降低以及纤连蛋白、6-酮-前列腺素F1α、蛋白C和总蛋白S浓度升高有关。与对照组相比，NPC 15669组抗凝血酶III的血浆浓度没有变化。NPC 15669后蛋白C、总蛋白S和6-酮-前列腺素F1α的增加（有利于抗血栓形成）以及内皮素-1和TxB2水平的降低（有利于血管舒张），可能解释了先前报道的该药物使梗死面积减小的原因。
