| ZD1611, an orally active endothelin-A receptor antagonist, prevents chronic hypoxia-induced pulmonary hypertension in the rat. | |
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MedLine Citation:
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PMID: 10545286 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article |
Journal Detail:
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Title: Pulmonary pharmacology & therapeutics Volume: 12 ISSN: 1094-5539 ISO Abbreviation: Pulm Pharmacol Ther Publication Date: 1999 |
Date Detail:
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Created Date: 2000-01-19 Completed Date: 2000-01-19 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9715279 Medline TA: Pulm Pharmacol Ther Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 303-12 Citation Subset: IM |
Copyright Information:
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Copyright 1999 Academic Press. |
Affiliation:
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Respiratory, Inflammatory and Neurological Diseases Research Section, ZENECA Pharmaceuticals, Wilmington, Delaware, 19850-5437, USA. russell.bialecki@phwilm.zeneca.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anesthesia Animals Anoxia / complications* Blood Gas Analysis Blood Pressure / drug effects Endothelin-1 / pharmacology Hematocrit Hypertension, Pulmonary / etiology*, prevention & control* Isometric Contraction / drug effects Male Muscle, Smooth, Vascular / pathology Organ Size / drug effects Pulmonary Artery / pathology Pulmonary Circulation / drug effects Pyrazines / pharmacology* Radioimmunoassay Rats Rats, Sprague-Dawley Receptor, Endothelin A Receptors, Endothelin / antagonists & inhibitors* Sulfonamides / pharmacology* Ventricular Function, Right / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Endothelin-1; 0/Pyrazines; 0/Receptor, Endothelin A; 0/Receptors, Endothelin; 0/Sulfonamides; 0/ZD 1611 |
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