Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors.
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.
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
J
J
Dupuis
C A
CA
Goresky
A
A
Fournier
D000768:Anesthesia, General; D000818:Animals; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006339:Heart Rate / Q000502:physiology; D008168:Lung / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000502:physiology; D017466:Receptors, Endothelin / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)