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.
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 mug/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 mug/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 mug/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.
Zhang
Jun
J
Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA. jun.zhang@fda.hhs.gov
Knapton
Alan
A
Lipshultz
Steven E
SE
Weaver
James L
JL
Herman
Eugene H
EH
D000319:Adrenergic beta-Antagonists / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D007124:Immunoenzyme Techniques; D007279:Injections, Subcutaneous; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020107:Troponin T / Q000097:blood*
D000319:Adrenergic beta-Antagonists; D020107:Troponin T; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007545:Isoproterenol