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Toxicologic Pathology
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Articles

Characterization of Troponin Responses in Isoproterenol-Induced Cardiac Injury in the Hanover Wistar Rat

Malcolm York1, Cheryl Scudamore1, Sally Brady2, Christabelle Chen2, Sharon Wilson1, Mark Curtis1, Gareth Evans3, William Griffiths4, Matthew Whayman1, Thomas Williams1 and John Turton2

1 GlaxoSmithKline Research and Development, Park Road, Ware, Herts SG12 0DP, UK
2 Centre for Toxicology, Department of Pharmacology, School of Pharmacy, University of London, London WC1N 1AX, UK
3 Safety Assessment Alderley, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
4 Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, London WC1N 1AX, UK

Correspondence: Address correspondence to: Cheryl Scudamore, GSK, R&D, Park Road, Ware, Herts SG12 0DP, UK; e-mail:cheryl.l.scudamore{at}gsk.com

The investigations aimed to evaluate the usefulness of cardiac troponins as biomarkers of acute myocardial injury in the rat. Serum from female Hanover Wistar rats treated with a single intraperitoneal (IP) injection of isoproterenol (ISO) was assayed for cardiac troponin I (cTnI) (ACS: 180SE, Bayer), cTnI (Immulite 2000, Diagnostic Products Corporation) and cardiac troponin T (cTnT) (Elecsys 2010, Roche). In a time-course study (50.0 mg/kg ISO), serum cTnI (ACS:180SE) and cTnT increased above control levels at 1 hour postdosing, peaking at 2 hours (cTnI, 4.30 µg/L; cTnT, 1.79 µg/L), and declined to baseline by 48 hours, with histologic cardiac lesions first seen at 4 hours postdosing. The Immulite 2000 assay gave minimal cTnI signals, indicating poor immunoreactivity towards rat cTnI. In a dose-response study (0.25 to 20.0 mg/kg ISO), there was a trend for increasing cTnI (ACS:180SE) values with increasing ISO dose levels at 2 hours postdosing. By 24 hours, cTnI levels returned to baseline although chronic cardiac myodegeneration was present. We conclude that serum cTnI and cTnT levels are sensitive and specific biomarkers for detecting ISO induced myocardial injury in the rat. Serum troponin values reflect the development of histopathologic lesions; however peak troponin levels precede maximal lesion severity.

Key Words: Cardiac troponin I • cardiotoxicity • isoproterenol • rat • toxicity • troponin

Abbreviations: ACPS, Advisory Committee for Pharmaceutical Sciences • ALT, Alanine aminotransferase • AST, Aspartate aminotransferase • CK, Total creatine kinase • CKBB, Creatine kinase isoenzyme BB • CKMB, Creatine kinase isoenzyme MB • CKMM, Creatine kinase isoenzyme, MM • cTn, Cardiac troponin • cTnI, Cardiac troponin I • cTnT, Cardiac troponin T • CV, Coefficient of variation • EWG, Expert Working Group • GLD, Glutamate dehydrogenase • H&E, Haematoxylin and eosin • IP, intraperitoneal • ISO, Isoproterenol • LD, Total lactate dehydrogenase • LD1 to LD5, Lactate dehydrogenase isoenzymes 1 to 5 • NAD, No abnormalities detected • NCSS, Nonclinical Studies Subcommittee • NS, Not statistically significant • OM, Original magnification • PBS, Phosphate-buffered saline • RT, Room temperature • SD, Standard deviation

Toxicologic Pathology, Vol. 35, No. 4, 606-617 (2007)
DOI: 10.1080/01926230701389316
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