Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Free Full Text Free
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Zhang, J.
Right arrow Articles by Sistare, F. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, J.
Right arrow Articles by Sistare, F. D.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Articles

Mechanisms and Biomarkers of Cardiovascular Injury Induced by Phosphodiesterase Inhibitor III SK&F 95654 in the Spontaneously Hypertensive Rat

Jun Zhang1
Eugene H. Herman1
Donald G. Robertson2
Michael D. Reily2
Alan Knapton1
Helen V. Ratajczak3
Nader Rifai4
Ronald Honchel1
Kerry T. Blanchard3
Raymond E. Stoll3
Frank D. Sistare1

1 Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993, USA
2 Metabonomics Evaluation Group, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA
3 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA
4 Department of Laboratory Medicine, Boston Childrens Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence: Address correspondence to: Jun Zhang, Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), 10903 New Hampshire Ave., Silver Spring, Maryland 20993, USA; e-mail:jun.zhang{at}fda.hhs.gov

The cardiovascular injury of the type III selective PDE inhibitor SK&F 95654 was investigated in SHR. Twenty-four hours after a single sc injection of 100 or 200 mg/kg of the drug, rats exhibited cardiomyocyte necrosis and apoptosis, interstitial inflammation, hemorrhage and edema, as well as mesenteric arterial hemorrhage and necrosis, periarteritis, EC and VSMC apoptosis, EC activation, and MC activation and degranulation. Elevated serum levels of cTnT and decreased cTnT immunoperoxidase staining on cardiomyocytes were detected in the drug-treated rats. Serum levels of {alpha}2-macroglobulin and IL-6 were significantly elevated following drug treatment. NMR spectral patterns of urine samples are significantly different between the drug-treated and control rats. These results indicate that measurement of serum cTnT, acute phase proteins, and cytokines as well as metabonomic urine profiles may serve as potential biomarkers for drug-induced cardiovascular injury in rats. Increased expression of CD63 on MC (tissue biomarker of MC), of nitrotyrosine on MC and EC (an indirect indicator of NO in vivo), and of iNOS on MC and EC (source of NO) suggest that NO produced by activated and degranulated MC as well as activated EC play an important role in SK&F 95654-induced mesenteric vascular injury.

Key Words: Cardiac troponin T • CD63 • inducible nitric oxide synthase • nitrotyrosine • mast cell degranulation • endothelial cell activation

Abbreviations: {alpha}2-M, {alpha}2-macroglobulin • cGMP, cyclic guanosine 3',5'-monophosphate • cTnT, cardiac troponin T • EC, vascular endothelial cells • iNOS, inducible nitric oxide synthase • MC, mesenteric tissue mast cells • NMR, nuclear magnetic resonance • NO, nitric oxide • PCA, principle component analysis • PDE, phosphodiesterase • SD, Sprague-Dawley rat • SHR, spontaneously hypertensive rat • TNF-{alpha}, tumor necrosis factor-{alpha} • VSMC, vascular smooth muscle cells

Toxicologic Pathology, Vol. 34, No. 2, 152-163 (2006)
DOI: 10.1080/01926230600588562
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
S. Korkmaz, V. Maupoil, C. Sobry, C. Brunet, S. Chevalier, and J.-L. Freslon
An Increased Regional Blood Flow Precedes Mesenteric Inflammation in Rats Treated by a Phosphodiesterase 4 Inhibitor
Toxicol. Sci., January 1, 2009; 107(1): 298 - 305.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
J. Zhang, R. D. Snyder, E. H. Herman, A. Knapton, R. Honchel, T. Miller, P. Espandiari, F. M. Goodsaid, I. Y. Rosenblum, J. P. Hanig, et al.
Histopathology of Vascular Injury in Sprague-Dawley Rats Treated with Phosphodiesterase IV Inhibitor SCH 351591 or SCH 534385
Toxicol Pathol, October 1, 2008; 36(6): 827 - 839.
[Abstract] [Full Text] [PDF]