Histopathological studies of microtubule disassembling agent-induced myocardial lesions in rats

Microtubule disassembling agents (MDAs) such as colchicine (COL) and vincristine sulfate (VCR) are known to be cardiotoxic. However, few attempts have been made to histopathologically examine cardiac lesions induced by MDAs. In this study, we endeavored to induce myocardial injury in rats by administering MDAs and to clarify the morphological features of these myocardial lesions. Male rats were intravenously administered COL (1.00 or 1.25mg/kg for 2 days at single daily doses) or VCR (0.50 or 0.75 mg/kg for 2 days at single daily doses). The day after administration, hearts were excised and examined histopathologically, immunohistochemically and electron microscopically. Degeneration and necrosis of myocardial cells with vacuolation were observed in rats administered COL at 1.25mg/kg or VCR at 0.75 mg/kg. Electron microscopic examination revealed vacuoles in swollen mitochondria. Moreover, there were cells showing pyknosis and karyorrhexis in the interstitium. TUNEL and immunohistochemical staining for endothelial cells and electron microscopic examination identified the apoptotic cells in the interstitium to be vascular endothelial cells. These vascular endothelial lesions were induced by lower doses of MDAs than were myocardial lesions. Furthermore, common sites of cardiac lesions induced by MDAs had almost the same distribution as areas positive for pimonidazole, a marker of hypoxia. These findings indicate that MDAs occasionally damage mitochondria in myocardial cells, and suggest that these changes involve microcirculatory dysfunction induced by endothelial cell injury.