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Toxicologic Pathology
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Contrast Medium- and Mannitol-Induced Apoptosis in Heart and Kidney of SHR Rats

Jun Zhang

Division of Applied Pharmacology Research, Center for Drug Evaluation and Research (HFD-910), Food and Drug Administration, Laurel, Maryland 20708, and

Cristobal G. Duarte

Division of Cardio-Renal Drug Products, Center for Drug Evaluation and Research (HFD-110), Food and Drug Administration, Rockville, Maryland 20857

Sydney Ellis

Division of Applied Pharmacology Research, Center for Drug Evaluation and Research (HFD-910), Food and Drug Administration, Laurel, Maryland 20708, and

The induction of apoptosis by contrast media (CM) and mannitol (M) was investigated in the hearts and kidneys of 12-mo-old male SHR rats. Ten groups of 3 SHR rats received a dose of 5 ml/kg of one of the following: Hypaque (H)-30. H-60, H-76, Omnipaque (O)-140, O-350, mannitol (M)-4%, M-9%, M-19%, M-27%, or saline (S). DNA fragmentation was detected using the terminal deoxynucleotidyl transferase-mediated [TdT] dUTP nick-end labeling (TUNEL) method, and the morphology characteristics of apoptosis were confirmed in cardiac and renal cells. The immunoreactivities of Bcl-2, Bax, and p53 were assessed immunohistochemically in the kidneys. Apoptosis occurred in cardiac myocytes and renal tubular and glomerular cells as well as in vascular endothelial and smooth muscle cells of the heart and kidneys. The high frequency of apoptosis correlated significantly with the increase in the osmolality of the H, O, and M. The increased Bax, the increased p53, and the decreased Bcl-2 immunoreactivities were detected in H- or O-treated, but not in M-treated, rats. These findings suggest that CM and M activate cardiac and renal apoptosis by different mechanisms and that the apoptotic process may be implicated in acute heart and renal damage.

Key Words: Cardiotoxicity • nephrotoxicity • terminal deoxynucleotidyl transferase-mediated [TdT] dUTP nick-end labeling (TUNEL) • Bcl-2 • Bax • p53 • osmolality

Toxicologic Pathology, Vol. 27, No. 4, 427-435 (1999)
DOI: 10.1177/019262339902700406
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