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Isoproterenol-induced Cardiotoxicity in Sprague-Dawley Rats: Correlation of Reversible and Irreversible Myocardial Injury with Release of Cardiac Troponin T and Roles of iNOS in Myocardial Injury

¹ Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA
² Department of Pediatrics, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA

Correspondence: Address correspondence to: Jun Zhang, M.D., M.S., Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration (HFD-910), Life Sciences Laboratory Building, Room 2082, 10903 New Hampshire Ave., Silver Spring, MD 20993–0002, USA; e-mail: jun.zhang{at}fda.hhs.gov.

The present study was undertaken to characterize myocardial lesions in the rat induced by low doses of isoproterenol (Iso) and to correlate lesion severity with release of cardiac troponin T (cTnT) and changes in myocyte iNOS expression. Two types of cardiac injury patterns were observed. A Type I response, noted 3 or 6 hours postdosing with 8, 16, 32, or 64 µg/kg Iso, included potential reversible myocardial alterations associated with slight increases in serum cTnT (< 0.3 ng/mL) and a slight reduction in myocyte cTnT immunoreactivity. The second type of response noted 3, 6, 12, 24 or 48 hours postdosing with 125, 250, or 500 µg/kg Iso consisted of irreversible myocyte alterations, together with significant increases in serum cTnT (3–14 ng/mL) and a marked reduction of cTnT immunoreactivity. By 48 hours the hearts of rats dosed with 125–500 µg/kg Iso had developed interstitial fibrosis, and serum cTnT had declined to near control levels (0.06–0.18 ng/mL). Increases in iNOS immunoreactivity correlated with the lesion severity. These findings suggest that low doses of Iso exert complex effects on the myocardium and that the generation of NO through increased expression of iNOS could be an important factor in the pathogenesis of myocyte injury.

Key Words: cardiac troponins • myocardial necrosis • myocardial apoptosis • iNOS

Abbreviations: BM, basement membrane • iNOS, inducible nitric oxide synthase • Iso, isoproterenol • cTnT, cardiac troponin T • cTnI, cardiac troponin I • NO, nitric oxide

This version was published on February 1, 2008

Toxicologic Pathology, Vol. 36, No. 2, 277-278 (2008)
DOI: 10.1177/0192623307313010


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