Jasmin Jean-François, Dupuis Jocelyn
Research Center, Montreal Heart Institute, and University of Montreal, Montreal, Quebec, Canada.
J Cardiovasc Pharmacol. 2004 Jan;43(1):21-5. doi: 10.1097/00005344-200401000-00004.
The endothelin-converting enzymes are distributed on both the surface of the endothelium and intracellularly. Whether circulating big-endothelin-1 can be hydrolyzed in plasma by lumen-bound endothelin-converting enzymes is unknown. The lung is the major site for hydrolysis of angiotensin-I to angiotensin-II by the angiotensin-converting enzyme; because of its high content in endothelin-converting enzymes, we hypothesized that the lung could similarly hydrolyze circulating big-endothelin-1. Since big-endothelin-1 produced by the lung can modulate coronary vascular tone, the heart may also have the capacity to hydrolyze circulating big-endothelin-1. Isolated lungs and hearts from Sprague-Dawley rats were perfused at 10 mL/min. Clearance of trace doses of human I125big-endothelin-1 was quantified using the indicator-dilution curves technique with labeled albumin as a vascular reference. Single-pass hydrolysis was assessed by bolus injection of human big-endothelin-1 (24 fmol) followed by serial ELISA determinations of big-endothelin-1 and endothelin-1 levels in effluent samples. To exclude possible uptake of produced endothelin-1, 10(-6) M BQ788 was added to the perfusate. The injections had no effect on perfusion pressures. There was no detectable clearance of I125big-endothelin-1 in the lung; however the heart extracted 14 +/- 1% of the injected tracer. There was no detectable big-endothelin-1 hydrolysis in the pulmonary as well as in the coronary circulations. The pulmonary circulation does not clear or hydrolyze circulating big-endothelin-1 suggesting that endothelin-converting enzymes are predominantly used for intracellular and/or abluminal conversion of locally produced big-endothelin-1. Mild coronary uptake of big-endothelin-1 suggests that this circulating peptide could modulate coronary vascular tone.
内皮素转换酶分布在内皮表面和细胞内。循环中的大内皮素 -1 是否能被管腔结合的内皮素转换酶在血浆中水解尚不清楚。肺是血管紧张素转换酶将血管紧张素 -I 水解为血管紧张素 -II 的主要部位；由于其内皮素转换酶含量高，我们推测肺可能同样能水解循环中的大内皮素 -1。由于肺产生的大内皮素 -1 可调节冠状动脉张力，心脏也可能有能力水解循环中的大内皮素 -1。以 10 mL/min 的速度灌注来自斯普拉格 - 道利大鼠的离体肺和心脏。使用标记白蛋白作为血管参考的指示剂稀释曲线技术对微量剂量的人 I125 大内皮素 -1 的清除率进行定量。通过推注人源大内皮素 -1（24 fmol），随后对流出样品中的大内皮素 -1 和内皮素 -1 水平进行连续酶联免疫吸附测定来评估单次通过水解。为排除产生的内皮素 -1 可能的摄取，在灌注液中加入 10(-6) M 的 BQ788。注射对灌注压力无影响。在肺中未检测到 I125 大内皮素 -1 的清除；然而，心脏摄取了 14±1%的注入示踪剂。在肺循环和冠状动脉循环中均未检测到可察觉的大内皮素 -1 水解。肺循环不清除或水解循环中的大内皮素 -1，这表明内皮素转换酶主要用于局部产生的大内皮素 -1 的细胞内和/或管腔外转化。大内皮素 -1 在冠状动脉中的轻度摄取表明这种循环肽可能调节冠状动脉张力。
