Document Detail


Endogenous endothelin in human coronary vascular function: differential contribution of endothelin receptor types A and B.
MedLine Citation:
PMID:  17353514     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET(A)) activation. However, the effects of selective endothelin receptor type B (ET(B)) and combined ET(A+B) receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and -independent vasomotor function before and after selective infusion of BQ-788 (an ET(B) receptor antagonist) or combined infusion of BQ-788+BQ-123 (an ET(A) antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation (P<0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123+BQ-788 dilated epicardial (P<0.0001) and resistance (P=0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123+BQ-788 (P=0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ-123+BQ-788. We conclude that selective ET(B) receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET(A+B) blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET(A) receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET(B) activation mediates vasodilation in human coronaries. Our data suggest that selective ET(A) blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis.
Authors:
Julian P J Halcox; Khaled R A Nour; Gloria Zalos; Arshed A Quyyumi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2007-03-12
Journal Detail:
Title:  Hypertension     Volume:  49     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-19     Completed Date:  2007-05-07     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1134-41     Citation Subset:  IM    
Affiliation:
Institute of Child Health, University College London, London, United Kingdom. j.halcox@ich.ucl.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Coronary Artery Disease / metabolism,  physiopathology*
Coronary Circulation / drug effects
Coronary Vessels / drug effects,  physiopathology*
Drug Combinations
Endothelin-1 / blood,  metabolism*
Endothelium, Vascular / physiopathology
Humans
Microcirculation / drug effects
Nitrogen Oxides / blood
Oligopeptides / pharmacology
Peptides, Cyclic / pharmacology
Pericardium
Piperidines / pharmacology
Receptor, Endothelin A / antagonists & inhibitors,  metabolism*
Receptor, Endothelin B / antagonists & inhibitors,  metabolism*
Vasoconstriction
Vasodilation
Vasomotor System / drug effects
Chemical
Reg. No./Substance:
0/BQ 788; 0/Drug Combinations; 0/Endothelin-1; 0/Nitrogen Oxides; 0/Oligopeptides; 0/Peptides, Cyclic; 0/Piperidines; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu)

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