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SK&F 95654-Induced Acute Cardiovascular Toxicity in Sprague-Dawley Rats—Histopathologic, Electron Microscopic, and Immunohistochemical Studies

Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, Maryland 20708

Eugene H. Herman

Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Hermaneu{at}cder.fda.gov

Alan Knapton

Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research

Douglas P. Chadwick

Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research

Virgil E. Whitehurst

Division of Pulmonary Drug Products (HFD-570)

John E. Koerner

Division of Cardio-Renal Drug Products (HFD-110)

Thomas Papoian

Division of Anesthetic, Critical Care, and Addiction Drug Products (HFD-170), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857

Victor J. Ferrans

Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892

Frank D. Sistare

Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research

The characteristics and pathogenesis of the cardiovascular toxicity induced by the type III selective phosphodiesterase inhibitor SK&F 95654 were examined in 2 studies. Sprague—Dawley rats received either a single sc injection of 50, 100, or 200 mg/kg SK&F 95654 and were euthanized at 24 hours after administration of the drug (Study 1), or were given a single subcutaneous (sc) injection of 100 mg/kg SK&F 95654 and euthanized at 1, 2, 4, 6, 8, 12, 24 hours, or 2 weeks after treatment (Study 2). Control rats received either DMSO or saline. Myocardial lesions and vascular lesions of the mesentery, spleen, and pancreas were seen 24 hours after dosing with either 50, 100, or 200 mg/kg SK&F 95654. The frequency and severity of these lesions (evaluated after the 100 mg/kg dose) increased with time over a period of 1 to 24 hours. By 2 weeks, the lesions subsided. Cardiac lesions consisted of myocyte necrosis with hypercontraction bands, inflammatory cell infiltration, interstitial hemorrhage, and interstitial edema. Vascular lesions of the mesentery were most prominent and consisted of vasodilatation and inflammation in the small-sized vessels, arterial medial necrosis and hemorrhage, and venous thrombosis. The vascular lesions included: leukocyte adhesion to endothelial cells, transendothelial migration of leukocytes, and inflammatory cell infiltration into vessel walls. Affected vessels included arteries, terminal arterioles, capillaries, postcapillary venules, and veins. Apoptosis of endothelial and smooth muscle cells was detected in the mesenteric vasculature by both TUNEL assay and electron microscopy. Evidence of endothelial cell activation in the mesenteric arteries and veins was also observed by electron microscopy. Immunohistochemical staining detected enhanced endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and von Willebrand factor (vWF) in the mesenteric arteries and veins. Mast cells were noted to be more prevalent in affected mesenteric tissue from drug-treated animals. The present findings suggest that apoptosis of endothelial and smooth muscle cells, activation of endothelial cells, recruitment of mast cells, and increased expression of adhesion molecules are important factors to the overall pathogenesis of SK&F 95654-induced vasculitis.

Key Words: Myocardial necrosis and inflammation • drug-induced vasculitis • vasodilatation • endothelial cell activation • endothelial and smooth muscle cell apoptosis • intercellular adhesion molecule-1 (ICAM-1) • von Willebrand factor • mast cell degranulation.

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Toxicologic Pathology, Vol. 30, No. 1, 28-40 (2002)
DOI: 10.1080/01926230252824680


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