Acute Coronary Artery Injury in Dogs Following Administration of CI-1034, an Endothelin A Receptor Antagonist

Abstract

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.

Myocardial and Reproductive System Toxicity of SCH 351591, a Selective Phosphodiesterase-4 Inhibitor, in CD-1 Mice

“…In other species, most notably rats (Zhang et al 2008) and monkeys (Losco et al 2004), the toxicity of PDE4 inhibitors has been closely linked to a primary vasculitis involving small to medium-sized muscular arteries, and any surrounding tissue involvement is considered secondary. Similar lesions, originating in the coronary arteries, have been reported for various vasoactive drugs in which the toxicity was attributed either to the pharmacologic effects of the compounds or to the local production of nitric oxide and pro-inflammatory chemokines (Jones et al 2003;McDuffie et al 2006;Mesfin et al 1989). The characteristic lesions reported in time-sequenced investigative studies included medial hemorrhage and necrosis followed by inflammation, smooth muscle proliferation, and fibrosis (Mesfin et al 1989).…”

Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents

“…However, CRP has not been useful as a predictor or a reporter of drug-induced vascular injury in rats, dog and/or monkeys. Other markers such as interleukin-6, and other cytokines have been suggested (McDuffie et al, 2004; Zhang et al, 2004) but these require further study. Adverse perturbation of the EC and activation of the immune system with subsequent inflammation can cause damage to SMC and EC.…”