Document Detail


Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung.
MedLine Citation:
PMID:  8929863     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3 (500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose to 1.9 +/- 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.
Authors:
D D Ivy; J W Ziegler; M F Dubus; J J Fox; J P Kinsella; S H Abman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Pediatric research     Volume:  39     ISSN:  0031-3998     ISO Abbreviation:  Pediatr. Res.     Publication Date:  1996 Mar 
Date Detail:
Created Date:  1997-02-06     Completed Date:  1997-02-06     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0100714     Medline TA:  Pediatr Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  435-42     Citation Subset:  IM    
Affiliation:
Sections of Cardiology, University of Colorado School of Medicine, Denver 80218, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Chronic Disease
Ductus Arteriosus / drug effects,  physiopathology
Endothelin-3 / pharmacology*
Female
Hemodynamics
Hypertension, Pulmonary / physiopathology*
Ligation
Lung / embryology,  physiopathology*
Peptides, Cyclic / pharmacology
Pregnancy
Receptors, Endothelin / metabolism*
Sheep
Time Factors
Grant Support
ID/Acronym/Agency:
46481//PHS HHS; H241012//PHS HHS
Chemical
Reg. No./Substance:
0/Endothelin-3; 0/Peptides, Cyclic; 0/Receptors, Endothelin; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu)

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