Early events in vascular injury in the rat induced by the phosphodiesterase IV inhibitor SCH 351591.
Treatment with drugs from multiple classes induces vascular injury with medial necrosis, hemorrhage, endothelial damage, and inflammation. Previous research has suggested early events might be occurring well in advance of the full lesions that appear forty-eight to seventy-two hours after dosing with SCH 351591, a PDE IV inhibitor. This study was performed to study early events in detail. Rats were dosed with 20 mg/kg of drug by gavage and sacrificed at times between fifteen and 240 minutes after dosing. Tissues were collected for histopathological analysis and gene expression studies. Serum was collected for biomarker analysis. The data from biomarker analysis showed a three-part response with an early phase that was maximal at fifteen to thirty minutes, a second phase from forty-five to 180 minutes, and the third phase that was starting to rise at four hours. The first phase included increases in lymphocytes, serum histamine, and serum nitrite. The second phase shows continued elevation of serum nitrite. The third phase was marked by an increase in serum GRO/CINC-1. At fifteen minutes, histopathology showed activation of mast cells, but not degranulation. Increases in endothelial activation and perivascular inflammatory cells were first apparent at thirty minutes and increased through 240 minutes.
Weaver
James L
JL
Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993-0002, USA. James.Weaver@fda.hhs.gov
Zhang
Jun
J
Knapton
Alan
A
Miller
Terry
T
Espandiari
Parvaneh
P
Smith
Roger
R
Gu
Yi-Zhong
YZ
Snyder
Ronald D
RD
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D003497:Cyclic N-Oxides / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008643:Mesentery / Q000098:blood supply / Q000473:pathology; D058988:Phosphodiesterase 4 Inhibitors / Q000633:toxicity*; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time; D057772:Vascular System Injuries / Q000097:blood / Q000139:chemically induced* / Q000473:pathology
D015415:Biomarkers; D003497:Cyclic N-Oxides; D058988:Phosphodiesterase 4 Inhibitors; D011804:Quinolines; C459379:SCH 351591