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Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom, Huw.Jones{at}AstraZeneca.com

Allen Macpherson

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Graham R. Betton

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

A. Stewart Davis

Animal Welfare Group, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Robert Siddall

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Peter Greaves

MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, United Kingdom

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 ETA 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.

Key Words: Arteritis • arteriopathy • vasculitis • dog • pathology • electron microscopy.

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