Document Detail

Endothelin receptor subtype distribution predisposes coronary arteries to damage.
MedLine Citation:
PMID:  10880383     Owner:  NLM     Status:  MEDLINE    
Several vasoactive drugs that lower blood pressure and increase heart rate induce regional cardiotoxicity in the dog, most frequently of right coronary arteries and right atrium. The basis for this selective damage is thought to result from local changes in vascular tone and blood flow. Administration of an endothelin receptor antagonist (ETRA, SB 209670) to dogs induced damage most frequent and severe in the right coronary artery and right atrium. Because site predisposition may correlate with distribution of vasoactive receptors, the objectives of this study were to map endothelin (ET) receptor distribution and density within regions of dog heart using both gene (mRNA) and protein expression endpoints for dog ET(A) and ET(B) receptors, and, additionally, correlate ET receptor subtype density with regional cardiac blood flow. A 10- to 15-mmHg reduction in mean arterial pressure with a concomitant increase in heart rate (10-20%), a six- and twofold increase in regional blood flow to the right and left atrium, respectively, and acute hemorrhage, medial necrosis, and inflammation were observed in the right coronary arteries and arteries of the right atrium after ETRA infusion for 5 days. Radioligand protein binding to quantify both ET receptors in normal dog heart indicated a twofold greater density of ET receptors in atrial regions versus ventricular regions. Importantly, ET receptor density in coronary arteries was markedly (about five- to sixfold) increased above that in atrial or ventricular tissues. ET receptor subtype characterization indicated ET(B) receptors were three times more prevalent in right coronary arteries compared to left coronary arteries and in situ hybridization confirmed localization of ET(B) in vascular smooth muscle. ET(A) receptor density was comparable in right and left coronary arteries. Quantitative real-time polymerase chain reaction for ET(A) and ET(B) receptor mRNA transcripts supported the site prevalence for message distribution. Consequently, the composite of protein and message expression profiles for ET(A) and ET(B) receptors indicated a disproportionate distribution of ET(B) receptors within right coronary artery of dog and this, along with functional measures of blood flow after ETRA infusion indicated a predisposition for exaggerated pharmacological responses and subsequent damage to right coronary arteries by ET and/or ETRAs.
C S Louden; P Nambi; M A Pullen; R A Thomas; L A Tierney; H A Solleveld; L W Schwartz
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The American journal of pathology     Volume:  157     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2000 Jul 
Date Detail:
Created Date:  2000-08-08     Completed Date:  2000-08-08     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  123-34     Citation Subset:  AIM; IM    
Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
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MeSH Terms
Amino Acid Sequence
Base Sequence
Coronary Disease / etiology,  metabolism*,  physiopathology
Coronary Vessels / drug effects,  metabolism,  pathology
Heart Atria / drug effects,  physiopathology
Heart Ventricles / drug effects,  physiopathology
Hemodynamics / drug effects
In Situ Hybridization
Indans / blood,  pharmacokinetics,  pharmacology
Molecular Sequence Data
RNA, Messenger / genetics,  metabolism
Receptors, Endothelin / antagonists & inhibitors,  genetics,  metabolism*
Regional Blood Flow / drug effects
Sequence Homology, Amino Acid
Sequence Homology, Nucleic Acid
Tissue Distribution
Reg. No./Substance:
0/Indans; 0/RNA, Messenger; 0/Receptors, Endothelin; 0I32BCL40Z/1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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