Pulmonary clearance of circulating endothelin-1 in dogs in vivo:
exclusive role of etb receptors.
Dupuis, Jocelyn, Carl A. Goresky, and Alain Fournier.
Departments of Medicine, Montreal Heart Institute, Montreal,
Quebec, Canada H1T 1C8, Montreal General Hospital, Montreal, Quebec,
Canada, H3G 1A4, and INRS-Sant[acute]e, Pointe-Claire, Quebec, Canada
H9R 1G6
APStracts 3:0276A, 1996.
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 (idiopathic,
heart failure, congenital anomalies and others) 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 BQ123 (n = 5,
120-960?nmol), and the specific ETB antagonist BQ788 (n = 6, 1000
nmol. The inhibitors had no significant effect on pulmonary and
systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was
not modified by BQ123 (control (C): 36 +/- 4%, antagonist (A): 34 +/-
6%) but was completely abolished by BQ788 (C: 34 +/- 6%, A: 0 +/- 2%,
P < 0.001). The pulmonary rate constant (K) for ET-1 removal was
also unaffected by BQ123 (C: 0.050 +/- 0.0085?s-1, A: 0.047 +/- 0.012
s-1) but significantly decreased and became close to zero after BQ788
(C: 0.058 +/- 0.014 s-1, A: 0.009 +/- 0.007 s-1, P < 0.001). We
conclude that the ETB receptor is completely and exclusively
responsible for pulmonary ET-1 removal in vivo. Future studies are
needed to show if desensitization or downregulation of the ETB
receptor may contribute to the increase in circulating ET-1 levels
found 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.
Received 24 January 1996; accepted in final form 31 May 1996.
APS Manuscript Number A82-6.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 28 June 96