title: Histopathology of vascular injury in Sprague-Dawley rats treated with phosphodiesterase IV inhibitor SCH 351591 or SCH 534385.
abstract: 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.
authors.affiliation: Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. jun.zhang@fda.hhs.gov
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Snyder
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Ronald
authors.initials: R
authors.lastname: Honchel
authors.forename: Terry
authors.initials: T
authors.lastname: Miller
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Federico M
authors.initials: FM
authors.lastname: Goodsaid
authors.forename: Irwin Y
authors.initials: IY
authors.lastname: Rosenblum
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.forename: James L
authors.initials: JL
authors.lastname: Weaver
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000633:toxicity*; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000098:blood supply / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D008638:Mesenteric Arteries / Q000473:pathology; D010179:Pancreas / Q000098:blood supply / Q000473:pathology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013270:Stomach / Q000098:blood supply / Q000473:pathology; D014652:Vascular Diseases / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D003497:Cyclic N-Oxides; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C459379:SCH 351591