Liuba Petru, Batra Satish, Pesonen Erkki, Werner Olof
Division of Pediatric Cardiology, University Hospital Lund, Sweden.
J Card Surg. 2005 Sep-Oct;20(5):420-4. doi: 10.1111/j.1540-8191.2005.2004120.x.
Arterial endothelial dysfunction is an important mechanism of tissue injury caused by ischemia-reperfusion (I/R). Earlier studies of I/R have shown that intracoronary preinfusion with 2.5-5 microg/mL bradykinin (BK) could alleviate the postischemic myocardial damage. Using an experimental human model of I/R, we investigated whether preceding infusion with BK could prevent the I/R-induced arterial endothelial dysfunction.
The left radial artery (LRA) from 16 healthy male adults, 18 to 30 years old, was submitted to I/R by completely occluding the left brachial artery with a pressure tourniquet for 20 minutes (ischemia), followed by its release (reperfusion). Prior to I/R, half of the subjects were randomly assigned to receive either BK (5 microg/mL) or saline, both being infused into the left brachial artery (0.5 mL/min, 10 min). The infusion was followed by a 10-minute drug-free period. The endothelial function of the LRA was studied by measuring the flow-mediated dilation (FMD) at baseline (prior to drug infusion), and at 15 minutes of reperfusion. In addition, baseline radial artery diameter, plasma nitrate, and von Willebrand factor were measured at these time points, and immediately before I/R (pre-I/R).
BK had no effect on the pre-I/R plasma nitrate (p > 0.5 vs. saline) and diameter of LRA (p > 0.5 vs. baseline). At 15 minutes of reperfusion, FMD was significantly decreased in the saline group as compared to baseline (absolute dilation: 0.08 +/- 0.03 vs. 3.02 +/- 0.8 mm, respectively, p < 0.01; percentage dilation: 3 +/- 0.6 vs. 8 +/- 0.6%, respectively, p < 0.001), but it remained unaffected in the BK group (absolute dilation: 3.06 +/- 0.9 vs. 3.27 +/- 0.8 mm, respectively, p > 0.5; percentage dilation: 7 +/- 0.7 vs. 8 +/- 0.8%, respectively, p > 0.5). A similar trend was observed with regard to plasma nitrate, which remained unchanged in the BK group (37.01 +/- 4.14 vs. 39.14 +/- 4.49 micromol/L, p > 0.5) but decreased in the saline group (35.91 +/- 3.03 vs. 28.91 +/- 2.81 micromol/L, p < 0.1).
Infusion of BK could protect the arterial endothelial function against I/R injury in humans, possibly in part by preserving the endothelial NO availability. The findings support the use of BK in the prevention of tissue injury due to I/R and might reveal an additional mechanism whereby ACE inhibitors exert their preconditioning effects on myocardium.
动脉内皮功能障碍是缺血再灌注（I/R）所致组织损伤的重要机制。早期关于I/R的研究表明，冠状动脉内预先输注2.5 - 5微克/毫升的缓激肽（BK）可减轻缺血后心肌损伤。我们使用I/R的人体实验模型，研究预先输注BK是否能预防I/R诱导的动脉内皮功能障碍。
选取16名年龄在18至30岁的健康男性成年人的左桡动脉（LRA），通过用压力止血带完全阻断左肱动脉20分钟（缺血），随后松开（再灌注）来进行I/R。在I/R之前，一半受试者被随机分配接受BK（5微克/毫升）或生理盐水，两者均注入左肱动脉（0.5毫升/分钟，共10分钟）。输注后有10分钟的无药期。通过在基线（药物输注前）和再灌注15分钟时测量血流介导的血管舒张（FMD）来研究LRA的内皮功能。此外，在这些时间点以及紧接I/R之前（I/R前）测量基线桡动脉直径、血浆硝酸盐和血管性血友病因子。
BK对I/R前的血浆硝酸盐（与生理盐水相比，p>0.5）和LRA直径（与基线相比，p>0.5）无影响。在再灌注15分钟时，与基线相比，生理盐水组的FMD显著降低（绝对舒张：分别为0.08±0.03与3.02±0.8毫米，p<0.01；舒张百分比：分别为3±0.6与8±0.6%，p<0.001），但BK组未受影响（绝对舒张：分别为3.06±0.9与3.27±0.8毫米，p>0.5；舒张百分比：分别为7±0.7与8±0.8%，p>0.5）。血浆硝酸盐也观察到类似趋势，BK组保持不变（37.01±4.14与39.14±4.49微摩尔/升，p>0.5），而生理盐水组降低（35.91±3.03与28.91±2.81微摩尔/升，p<0.1）。
输注BK可保护人体动脉内皮功能免受I/R损伤，可能部分是通过维持内皮一氧化氮的可用性。这些发现支持使用BK预防I/R所致组织损伤，并可能揭示血管紧张素转换酶抑制剂对心肌发挥预处理作用的另一种机制。
