Document Detail

ZD1611, an orally active endothelin-A receptor antagonist, prevents chronic hypoxia-induced pulmonary hypertension in the rat.
MedLine Citation:
PMID:  10545286     Owner:  NLM     Status:  MEDLINE    
Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen implicated in the pathogenesis of pulmonary hypertension (PH). We evaluated the effects of an ET(A)receptor-selective antagonist, ZD1611, on hypoxia-induced PH in rats. <<Prophylactic>> and <<therapeutic>> paradigms were established in which rats were administered placebo or ZD1611 (1-3 mg/kg, q.i.dpo) concomitant with hypoxic exposure (10% O(2)1 ATM) for 14 days or beginning after 7-day hypoxic exposure for 21 days. Compared with normoxic controls, hypoxic exposure plus placebo increased (P<0.05) hematocrit, mass ratio of right ventricle over left ventricle plus septum (RV/LV+S), and right intraventricular peak systolic pressure (RVSP). These latter two effects were decreased (P<0.05) by ZD1611 in both experimental paradigms [RV/LV+S(%)::RVSP(%); prophylactic, 14::32; therapeutic, 28::37]. Hypoxic exposure did not change mean systemic arterial pressure (MSAP). ZD1611 did not affect MSAP, plasma ET-1 concentrations, or blood gases measured when rats respired room air. In mechanistic studies, ZD1611 decreased (P<0.01) smooth muscle hypertrophy of small pulmonary arteries and abolished hypoxia-induced decreases in sensitivity and maximum contraction to ET-1 in isolated extralobar branch pulmonary artery. In conclusion, the ET(A)receptor-selective antagonist, ZD1611, attenuates hypoxia-induced PH in the rat.
R A Bialecki; C S Fisher; B M Abbott; H G Barthlow; R G Caccese; R B Stow; J Rumsey; W Rumsey
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pulmonary pharmacology & therapeutics     Volume:  12     ISSN:  1094-5539     ISO Abbreviation:  Pulm Pharmacol Ther     Publication Date:  1999  
Date Detail:
Created Date:  2000-01-19     Completed Date:  2000-01-19     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9715279     Medline TA:  Pulm Pharmacol Ther     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  303-12     Citation Subset:  IM    
Copyright Information:
Copyright 1999 Academic Press.
Respiratory, Inflammatory and Neurological Diseases Research Section, ZENECA Pharmaceuticals, Wilmington, Delaware, 19850-5437, USA.
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MeSH Terms
Anoxia / complications*
Blood Gas Analysis
Blood Pressure / drug effects
Endothelin-1 / pharmacology
Hypertension, Pulmonary / etiology*,  prevention & control*
Isometric Contraction / drug effects
Muscle, Smooth, Vascular / pathology
Organ Size / drug effects
Pulmonary Artery / pathology
Pulmonary Circulation / drug effects
Pyrazines / pharmacology*
Rats, Sprague-Dawley
Receptor, Endothelin A
Receptors, Endothelin / antagonists & inhibitors*
Sulfonamides / pharmacology*
Ventricular Function, Right / drug effects
Reg. No./Substance:
0/Endothelin-1; 0/Pyrazines; 0/Receptor, Endothelin A; 0/Receptors, Endothelin; 0/Sulfonamides; 0/ZD 1611

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