Acute coronary artery injury in dogs following administration of CI-1034, an endothelin A receptor antagonist.
The objective of this study was to characterize acute coronary artery injury evoked by the endothelin A receptor (ETAR) antagonist, CI-1034. Male dogs (n = 5) were intravenously administered CI-1034 at 120 mg/kg for 4 d. Control animals (n = 3) received vehicle. Macroscopically, drug-related hemorrhage was observed in the right coronary groove and atrium. Histologically, drugrelated coronary changes were characterized as medial hemorrhage and necrosis, with mixed inflammatory-cell infiltrates in the adventitia and media. Immunohistochemistry staining indicated increased expression of inducible nitric oxide synthase (iNOS), cleaved caspase-3, and S100A8/A9 (within in monocytes and neutrophils) proteins in coronary arteries of CI-1034-treated animals. However, there were similar expression levels of endothelial nitric oxide synthase (eNOS) among control and CI-1034-treated animals. Significant drug-related nitric oxide (NO) accumulation occurred on days 1 through 4 in serum. Increased interleukin (IL)-6 and fibrinogen in plasma and serum amyloid A (SAA) occurred on days 2 through 5 in CI-1034-treated animals. Increased levels of NO accumulation in serum; increased IL-6 and fibrinogen levels in plasma; increased SAA levels; and increased expressions of iNOS, cleaved caspase-3, and S100A8/A9 complex appear to be characteristic of CI-1034-induced acute vascular injury in dogs.
McDuffie
J Eric
JE
Esperion Therapeutics, a Division of Pfizer Global Research and Development, Drug Safety Evaluation, Plymouth, MI 48170, USA. eric.mcduffie@pfizer.com
Yu
Xinwen
X
Sobocinski
Gregg
G
Song
Yunling
Y
Chupka
Jonathan
J
Albassam
Mudher
M
D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D065130:Endothelin A Receptor Antagonists; D005340:Fibrinogen / Q000032:analysis; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009336:Necrosis; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013843:Thiazines / Q000633:toxicity*; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D040501:Calgranulin A; D040502:Calgranulin B; D065130:Endothelin A Receptor Antagonists; D015850:Interleukin-6; C419982:PD 180988; D013843:Thiazines; D009569:Nitric Oxide; D005340:Fibrinogen; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D020169:Caspases