title: Coronary and systemic arterial physiology and immunohistochemical markers related to early coronary arterial lesions in beagle dogs given the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611.
abstract: We evaluated immunohistochemistry (von Willebrand Factor [vWF] or fibrinogen) and systemic and coronary arterial physiological parameters in beagle dogs to investigate early arterial lesions induced by the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611. Dogs given an oral dose of ZD6169 (experiment 1) were terminated 1 day later and showed arterial and myocardial lesions. Minimal arterial lesions exhibited few condensed medial smooth muscle cells only, with others showing segmental medial necrosis occasionally with medial/adventitial acute inflammation. Intercellular immunostaining was seen in ostensibly normal tissue, where no pathology was present in conventionally stained sections. vWF and fibrinogen are valuable tools for detecting disruption of arterial integrity. In experiment 2, 2 dogs were given a single high dose of ZD6169 or ZD1611 and BP/HR monitored by conventional measures or telemetry. Substantially reduced systolic/diastolic BP and increased HR occurred within 10 min of ZD6169 infusion: ZD1611 caused minor BP decrease and HR increase. In experiment 3, both drugs given to anaesthetized dogs induced markedly exaggerated systolic phasic forward and reverse flow in left descending and right coronary arteries. Diastolic coronary artery flows were unaffected with ZD1611 and increased slightly with ZD6169. In both coronary arteries, the ZD1611-induced increase in flows paralleled decreased resistance.
authors.affiliation: Global Safety Assessment, AstraZeneca Pharmaceuticals, Cheshire SK10 4TG, United Kingdom. huw.jones@astrazeneca.com
authors.forename: Huw Bowen
authors.initials: HB
authors.lastname: Jones
authors.forename: Jan-Arne
authors.initials: JA
authors.lastname: Björkman
authors.forename: Jason
authors.initials: J
authors.lastname: Schofield
mesh_terms: D000577:Amides / Q000633:toxicity*; D000818:Animals; D001167:Arteritis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D001577:Benzophenones / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000737:chemistry* / Q000473:pathology*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D009206:Myocardium / Q000473:pathology; D011719:Pyrazines / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000577:Amides; D001577:Benzophenones; D015415:Biomarkers; D011719:Pyrazines; D013449:Sulfonamides; C121226:ZD 1611; C095007:Zeneca ZD 6169; D014841:von Willebrand Factor; D005340:Fibrinogen
keywords: ZD1611; ZD6169; arteritis.; beagle dog; drug-induced vascular injury; endothelin receptor antagonist; potassium channel opener