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.