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Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385
1 Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA Correspondence: Jun Zhang, M.D., M.S., Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA; e-mail:jun.zhang{at}fda.hhs.gov. Histopathological and immunohistochemical studies were conducted to characterize vascular injuries in rats treated with phosphodiesterase (PDE) IV inhibitors SCH 351591 or SCH 534385. Sprague-Dawley rats were administered PDE IV inhibitors by gavage at a range of doses and times. The two PDE IV inhibitors induced comparable levels of vascular injury, primarily in the mesentery and to a lesser extent in the pancreas, kidney, liver, small intestine, and stomach. Mesenteric vascular changes occurred as early as one hour, progressively developed over twenty-four to forty-eight hours, peaked at seventy-two hours, and gradually subsided from seven to nine days. The typical morphology of the vascular toxicity consisted of hemorrhage and necrosis of arterioles and arteries, microvascular injury, fibrin deposition, and perivascular inflammation of a variety of blood vessels. The incidence and severity of mesenteric vascular injury increased in a time- and dose-dependent manner in SCH 351591- or SCH 534385-treated rats. Mesenteric vascular injury was frequently associated with activation of mast cells (MC), endothelial cells (EC), and macrophages (MØ). Immunohistochemical studies showed increases in CD63 immunoreactivity of mesenteric MC and in nitrotyrosine immunoreactivity of mesenteric EC and MØ. The present study also provides a morphological and cellular basis for evaluating candidate biomarkers of drug-induced vascular injury.
Key Words: activation and degranulation of mast cell • activation of endothelial cell and macrophage • apoptosis of endothelial and smooth muscle cells • arterial hemorrhage and necrosis • nitrotyrosine • peroxynitrite Abbreviations: bFGF, basic fibroblast growth factor • EC, endothelial cell • iNOS, inducible nitric oxide synthase • MØ, macrophage • MC, mast cells • mkd, mg/kg/day • NO, nitric oxide • PDE, phosphodiesterase • PTAH, phosphotungstic acid hematoxylin stain • SMC, vascular smooth muscle cell
This version was published on October
1, 2008 Toxicologic Pathology, Vol. 36, No. 6,
827-839 (2008) This article has been cited by other articles:
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