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Early myocardial lesions induced by cardiotoxic compounds in Sprague-Dawley rats
M Kemi1, H Matsumoto, Y Nomura
1Department of Safety Assessment, Bonya Pharmaceutical Co., Ltd., Saitama, Japan.
Abstract:
Early focal myocardial lesions in rats induced by five cardiotoxic compounds were histopathologically observed 1 hr and 4 hr after a single intravenous injection with 1/10 LD50 and LD50. The lesions were observed 1 hr and 4 hr after the treatment with LD50 of isoproterenol (ISP), 4 hr with 1/10 LD50 of ISP, 4 hr with LD50 of hydralazine (HYD), caffeine (CAF) and cyclophosphamide (CYC), but not with adriamycin (ADR). The lesions consisted of homogeneously intensely eosinophilic staining, contraction band formation and fragmentation of cardiac muscle fibers. The lesions were interspersed in the inner one third of the left ventricular walls including the papillary muscles with ISP, HYD and CAF, and were all over the ventricular myocardium with CYC.
Insights
Early heart muscle damage from cardiotoxic compounds like isoproterenol was observed in rats. Histopathology revealed specific lesions in cardiac fibers, varying by compound and dosage.
Area of Science:
- Toxicology
- Cardiovascular Pathology
- Drug-Induced Injury
Background:
- Cardiotoxicity is a significant concern with various therapeutic agents and environmental toxins.
- Understanding the early histopathological changes induced by cardiotoxic compounds is crucial for risk assessment and developing countermeasures.
- Previous studies have identified several compounds with potential cardiotoxic effects, but detailed early lesion characterization is often limited.
Purpose of the Study:
- To investigate and characterize the early focal myocardial lesions induced by five distinct cardiotoxic compounds in a rat model.
- To determine the time course and dose-dependency of these histopathological changes.
- To compare the lesion patterns caused by different cardiotoxic agents.
Main Methods:
- Rats were administered single intravenous injections of five cardiotoxic compounds: isoproterenol (ISP), hydralazine (HYD), caffeine (CAF), cyclophosphamide (CYC), and adriamycin (ADR).
- Doses administered were 1/10 LD50 and LD50 for each compound.
- Cardiac tissues were collected and examined histopathologically at 1 hour and 4 hours post-injection.
Main Results:
- Early focal myocardial lesions were observed in rats treated with ISP, HYD, CAF, and CYC, but not ADR.
- Lesions appeared as homogeneously intensely eosinophilic staining, contraction band formation, and fragmentation of cardiac muscle fibers.
- The distribution of lesions varied: ISP, HYD, and CAF primarily affected the inner one-third of the left ventricular walls and papillary muscles, while CYC induced lesions throughout the ventricular myocardium.
Conclusions:
- Isoproterenol, hydralazine, caffeine, and cyclophosphamide induce characteristic early focal myocardial lesions in rats.
- Adriamycin did not show early cardiotoxic effects under the tested conditions.
- The specific histopathological features and distribution patterns of these lesions provide insights into the mechanisms of cardiotoxicity for different compounds.