| Endothelin antagonist-induced coronary and systemic arteritis in the beagle dog. | |
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MedLine Citation:
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PMID: 12746113 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Two endothelin antagonists, ZD1611 (3-[4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl]-2,2-dimethylpropanoic acid) and ZD2574 (2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide), selective for the ET(A) receptor and intended for use in pulmonary hypertension, were tested in Beagle dogs at various doses for periods of up to 4 weeks. These studies included in vivo telemetric hemodynamic assessment, full histopathological and ultrastructural pathological evaluation of coronary arteries. Both drugs produced arteritis in small- and medium-sized coronary arteries after single or multiple doses, some of which were at or below the ED50. The distribution of lesions was predominantly in extramural arteries over the atria and atrioventricular groove of the right side of the heart and consisted of epicardial hemorrhage and arteritis. Systemic arteritis was also present at a lower incidence than the coronary arteritis, was located at different sites and appeared inconsistently. Ultrastructural changes in coronary arteries suggested that damage was the result of mechanical factors. Although these patterns of vascular injury possessed features in common with those induced in dogs by high doses of vasodilating antihypertensive drugs and inotropic agents, they were atypical, as there was no left ventricular myocardial necrosis, papillary muscle damage, or subendocardial hemorrhage suggestive of ischaemia or excessive inotropism. Moreover, physiological monitoring showed no evidence of exaggerated systemic hypotension or reflex tachycardia at doses associated with vascular damage. Consequently, the changes might be the result of a localized pharmacological process such as intense, prolonged vasodilatation in unsupported arteries that are well endowed with endothelin receptors and particularly sensitive to endothelin antagonism. |
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Authors:
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Huw B Jones; Allen Macpherson; Graham R Betton; A Stewart Davis; Robert Siddall; Peter Greaves |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Toxicologic pathology Volume: 31 ISSN: 0192-6233 ISO Abbreviation: Toxicol Pathol Publication Date: 2003 May-Jun |
Date Detail:
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Created Date: 2003-05-14 Completed Date: 2004-01-20 Revised Date: 2009-07-01 |
Medline Journal Info:
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Nlm Unique ID: 7905907 Medline TA: Toxicol Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 263-72 Citation Subset: IM |
Affiliation:
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Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom. Huw.Jones@AstraZeneca.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta, Abdominal / ultrastructure Arteritis / chemically induced*, pathology Blood Pressure / drug effects Coronary Vessels / ultrastructure* Dogs Electrocardiography Female Hypertension, Pulmonary / drug therapy Male Microscopy, Electron Photomicrography Pyrazines / adverse effects*, therapeutic use Receptor, Endothelin A / antagonists & inhibitors* Sulfonamides / adverse effects*, therapeutic use |
| Chemical | |
Reg. No./Substance:
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0/Pyrazines; 0/Receptor, Endothelin A; 0/Sulfonamides; 0/ZD 1611; 0/ZD 2574 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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