Battistini B, Kingma J G
Centre de recherche, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie, Department of Medicine, Laval University, Ste-Foy, Quebec, Canada.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S215-20.
Upregulation of the endothelin (ET) system, following coronary ischemia-reperfusion injury, may contribute to coronary vasospasm and congestive heart failure. Because endothelin-1 (ET-1) is rapidly cleared from the circulation, the levels of its inactive precursor big ET-1 and the ET-1/big ET-1 ratio may constitute better ways to assess the activation of the ET system in both venous and arterial beds. Anesthetized dogs (n = 6-12) were subjected to two successive coronary artery occlusions (with intervening 60 min reperfusion) over 6 h. Cardiac hemodynamics and electrocardiogram (ECG) were recorded and blood samples were drawn simultaneously from the internal thoracic artery and coronary sinus (venous blood). Under basal conditions at t = -20 min, arterial plasma levels of ET-1 and big ET-1 were 2.05 +/- 0.21 and 2.00 +/- 0.51 pg/ml (ratio: 1.00; n = 12); venous values were 2.29 +/- 0.25 and 3.14 +/- 0.77, respectively (ratio: 0.73, n = 12). Both arterial and venous plasma levels of ET-1 increased (by 46 and 56%) after 5 and 15 min of reperfusion, respectively, following the initial 120 min ischemic period compared to baseline values, and returned to near baseline values after 60 min reperfusion. Both arterial and venous values for big ET-1 increased steadily by 2.2 and 2.3 times maximum, respectively, during the initial 60 min reperfusion period; these values increased by 3.4 and 3.2 times, respectively by the end of the second 120 min reperfusion period. ET-1/big ET-1 ratios dropped to 0.39, in arterial, and 0.21, in venous plasma, at the end of the second reperfusion period. In conclusion, plasma ET-1 levels increase significantly but transiently after the first ischemic injury; the increased plasma big ET-1 levels were more pronounced in both the arterial and venous circulation along with ischemia-reperfusion injuries. These results suggest an upregulation of the ET system that was easily monitored by increased production of big ET-1. During ischemia-reperfusion injuries, the conversion to the active mature peptide ET-1 is either impaired, or ET-1 is more rapidly degraded.
冠状动脉缺血再灌注损伤后内皮素（ET）系统上调，可能导致冠状动脉痉挛和充血性心力衰竭。由于内皮素-1（ET-1）可迅速从循环中清除，其无活性前体大内皮素-1的水平以及ET-1/大内皮素-1比值可能是评估静脉和动脉床中ET系统激活的更好方法。将麻醉犬（n = 6 - 12）在6小时内进行两次连续的冠状动脉闭塞（中间间隔60分钟再灌注）。记录心脏血流动力学和心电图（ECG），并同时从胸内动脉和冠状窦（静脉血）采集血样。在基础状态下（t = -20分钟），动脉血浆中ET-1和大内皮素-1的水平分别为2.05±0.21和2.00±0.51 pg/ml（比值：1.00；n = 12）；静脉值分别为2.29±0.25和3.14±0.77（比值：0.73，n = 12）。在最初120分钟缺血期后的再灌注5分钟和15分钟后，动脉和静脉血浆中ET-1水平分别升高（46%和56%），与基线值相比，再灌注60分钟后恢复到接近基线值。在最初60分钟再灌注期内，动脉和静脉中大内皮素-1的值分别稳定增加至最大值的2.2倍和2.3倍；在第二个120分钟再灌注期结束时，这些值分别增加3.4倍和3.2倍。在第二个再灌注期结束时，动脉血浆中ET-1/大内皮素-1比值降至0.39，静脉血浆中降至0.21。总之，首次缺血损伤后血浆ET-1水平显著但短暂升高；随着缺血再灌注损伤，动脉和静脉循环中血浆大内皮素-1水平升高更为明显。这些结果表明ET系统上调，可通过大内皮素-1生成增加来轻松监测。在缺血再灌注损伤期间，向活性成熟肽ET-1的转化受损，或者ET-1降解更快。
