Dupuis J, Goresky C A, Fournier A
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
J Appl Physiol (1985). 1996 Oct;81(4):1510-5. doi: 10.1152/jappl.1996.81.4.1510.
The pulmonary circulation plays an important role in the removal of circulating endothelin-1 (ET-1). Plasma ET-1 levels are increased in pulmonary hypertensive states of various etiologies (e.g., idiopathic, heart failure, and congenital anomalies) in proportion to the severity of pulmonary hypertension. It is possible that reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia of those pathologies. The ETA and ETB receptors are abundant in lung tissues: on the vascular endothelium, the ETB receptor is predominant and may contribute to ET-1 extraction through receptor-mediated endocytosis. We designed experiments to determine and quantify the importance of the ETA and ETB receptors in the pulmonary extraction of circulating ET-1 in anesthetized dogs. The single-pass cumulative tracer ET-1 extraction by the lung was measured with the indicator-dilution technique before and 5 min after intrapulmonary injection of the specific ETA antagonist BQ-123 (n = 5, 120-960 nmol) and the specific ETB antagonist BQ-788 (n = 6, 1,000 nmol). The inhibitors had no significant effect on pulmonary and systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was not modified by BQ-123 [control (C): 36 +/- 4%, antagonist (A): 34 +/- 6%] but was completely abolished by BQ-788 (C: 34 +/- 6%, A: 0 +/- 2%, P < 0.001). The pulmonary rate constant (K) for ET-1 removal was also unaffected by BQ-123 (C: 0.050 +/- 0.0085 s-1, A: 0.047 +/- 0.012 s-1) but significantly decreased and became close to zero after BQ-788 (C: 0.058 +/- 0.014 s-1, A: 0.009 +/- 0.007 s-1, P < 0.1). We conclude that the ETB receptor is completely and exclusively responsible for pulmonary ET-1 removal in vivo. Future studies are needed to show whether desensitization or downregulation of the ETB receptor may contribute to the increase in circulating ET-1 levels in conditions associated with pulmonary hypertension. This novel pulmonary endothelial cell function may play a protective role by modulating circulating ET-1 levels in the systemic circulation.
肺循环在清除循环中的内皮素 -1（ET-1）方面发挥着重要作用。在各种病因导致的肺动脉高压状态（如特发性、心力衰竭和先天性异常）下，血浆ET-1水平会随着肺动脉高压的严重程度成比例升高。这种肽的肺清除率降低可能导致这些疾病的高内皮素血症。ETA和ETB受体在肺组织中大量存在：在血管内皮上，ETB受体占主导地位，可能通过受体介导的内吞作用促进ET-1的摄取。我们设计了实验，以确定和量化ETA和ETB受体在麻醉犬肺循环中对循环ET-1摄取的重要性。在肺内注射特异性ETA拮抗剂BQ-123（n = 5，120 - 960 nmol）和特异性ETB拮抗剂BQ-788（n = 6，1000 nmol）之前及之后5分钟，采用指示剂稀释技术测量肺对单次通过的累积示踪剂ET-1的摄取。这些抑制剂对肺和全身血流动力学无显著影响。BQ-123对平均累积肺ET-1摄取无影响（对照（C）：36±4%，拮抗剂（A）：34±6%），但BQ-788完全消除了这种摄取（C：34±6%，A：0±2%，P < 0.001）。ET-1清除的肺速率常数（K）也不受BQ-123影响（C：0.050±0.0085 s-1，A：0.047±0.012 s-1），但在注射BQ-788后显著降低并接近零（C：0.058±0.014 s-1，A：0.009±0.007 s-1，P < 0.1）。我们得出结论，ETB受体在体内完全且唯一地负责肺对ET-1的清除。未来需要开展研究，以确定ETB受体的脱敏或下调是否可能导致与肺动脉高压相关疾病中循环ET-1水平的升高。这种新发现的肺内皮细胞功能可能通过调节体循环中循环ET-1的水平发挥保护作用。
