Pulmonary clearance of circulating endothelin-1 in dogs in vivo: Exclusive role of ET(B) receptors
Pulmonary clearance of circulating endothelin-1 in dogs in vivo: Exclusive role of ET(B) receptors
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DOI：
10.1152/jappl.1996.81.4.1510
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发表时间：
1996-10-01
影响因子：
3.3
通讯作者：
Fournier, A
中科院分区：
文献类型：
--
作者：
Dupuis, J;Goresky, CA;Fournier, A
肺循环在循环内皮素-1 (ET-1) 的清除中起着重要作用。在各种病因（例如特发性、心力衰竭和先天性异常）的肺动脉高压状态下，血浆 ET-1 水平升高，与肺动脉高压的严重程度成比例。该肽的肺部清除率降低可能导致这些病理的高内皮素血症。 ET(A) 和 ET(B) 受体在肺组织中丰富：在血管内皮上，ET(B) 受体占主导地位，可能有助于通过受体介导的内吞作用提取 ET-1。我们设计了实验来确定和量化 ET(A) 和 ET(B) 受体在麻醉犬循环 ET-1 肺部提取中的重要性。在肺内注射特异性 ET(B) 拮抗剂 BQ-123 (n = 5, 120-960 nmol) 和特异性 ET(B) 拮抗剂 BQ-788 (n = 6, 1,000 nmol) 之前和之后 5 分钟，使用指示剂稀释技术测量肺部单次累积示踪剂 ET-1 提取量。抑制剂对肺和全身血流动力学没有显着影响。 BQ-123 未改变平均累积肺 ET-1 提取量 [对照 (C)：36 +/- 4%，拮抗剂 (A)：34 +/- 6%]，但被 BQ-788 完全消除（C：34 +/- 6%，A：0 +/- 2%，P < 0.001）。去除 ET-1 的肺速率常数 (K) 也不受 BQ-123 的影响 (C: 0.050 +/- 0.0085 s(-1), A: 0.047 +/- 0.012 s(-1))，但在 BQ-788 后显着下降并接近于零 (C: 0.058 +/- 0.014 s(-1), A: 0.009 +/- 0.007 秒(-1)，P < 0.001)。我们得出的结论是，ET(B) 受体完全且专门负责体内肺部 ET-1 的去除。未来的研究需要证明 ET(B) 受体脱敏或下调是否可能导致肺动脉高压相关疾病中循环 ET-1 水平的增加。这种新的肺内皮细胞功能可能通过调节体循环中的循环 ET-1 水平发挥保护作用。
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 ET(A) and ET(B) receptors are abundant in lung tissues: on the vascular endothelium, the ET(B) 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 ET(A) and ET(B) 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 ET(B) antagonist BQ-123 (n = 5, 120-960 nmol) and the specific ET(B) 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 < 0.001). We conclude that-the ET(B) 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 ET(B) 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.