Bains A S, Scalia R, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Eur J Pharmacol. 1998 Aug 28;356(1):67-72. doi: 10.1016/s0014-2999(98)00521-4.
We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.
我们利用大鼠肠系膜活体显微镜技术，研究了新型丝氨酸蛋白酶抑制剂LEX032对N（G）-硝基-L-精氨酸甲酯（L-NAME）诱导的体内白细胞与内皮细胞相互作用的影响。与用Krebs-Henseleit（K-H）溶液灌注的对照大鼠相比，用50微摩尔/升L-NAME（一种一氧化氮（NO）抑制剂）灌注大鼠肠系膜90分钟，导致白细胞滚动、白细胞黏附和白细胞迁移显著且随时间增加。然而，对L-NAME灌注的大鼠全身给予LEX032（15毫克/千克推注，随后每小时输注15毫克/千克），可显著减弱大鼠肠系膜小静脉内皮上的白细胞滚动和黏附，并抑制白细胞通过微血管内皮壁的迁移。此外，全身给予LEX032后，平均动脉血压或局部小静脉剪切率未观察到显著变化。我们的数据表明，LEX032对丝氨酸蛋白酶的全身抑制作用可减少因抑制NO合成而引发的增强的白细胞与内皮细胞相互作用。这些结果也解释了丝氨酸蛋白酶抑制剂在缺血再灌注和其他炎症状态下发挥的一些有益作用。
