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Effects of seven anthracycline antibiotics on electrocardiogram and mitochondrial function of rat hearts
Abstract:
Daunomycin, adriamycin and 5 semisynthetic anthracycline antibiotics inhibited oxygen consumption or ATP production of rat heart mitochondria in vitro. The no-effect levels varied depending on the substrate used and ranged from 1 nmole per mg mitochondrial protein. Mitochondrial functions were also studied in hearts of rats treated with repeated i.p. injections of the 7 antibiotics. Decrease in oxygen consumption without change in ATP production was observed with adriamycin and NSC-149584. Daunomycin, NSC-164011, NSC-143496 NSC-143114 affected primarily ATP production. The most potent compounds were daunomycin and adriamycin which damaged mitochondrial function at cummulative doses of approximately 10 mg/kg. ECGs were monitored in groups of equally treated rats. Cardiotoxicity manifested itself by progressive widening of the QRS complex often followed by the development of a S-wave trough. The most toxic compounds also induced intraventricular block, bradycardia and heart failure. The development of the ECG changes showed a good correlation with the impairment of mitochondrial function.
Insights
Anthracycline antibiotics like daunomycin and adriamycin impair rat heart mitochondrial function, affecting oxygen consumption and ATP production. This mitochondrial damage correlates with electrocardiogram changes, indicating cardiotoxicity.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiology
Background:
- Anthracycline antibiotics are widely used chemotherapy agents.
- Cardiotoxicity is a significant dose-limiting side effect of anthracycline therapy.
- The precise mechanisms underlying anthracycline-induced cardiotoxicity remain under investigation.
Purpose of the Study:
- To investigate the in vitro and in vivo effects of daunomycin, adriamycin, and related anthracycline antibiotics on rat heart mitochondrial function.
- To correlate mitochondrial dysfunction with electrocardiogram (ECG) changes indicative of cardiotoxicity.
Main Methods:
- In vitro assessment of mitochondrial oxygen consumption and ATP production in response to anthracycline exposure.
- In vivo administration of anthracyclines to rats followed by mitochondrial function analysis and ECG monitoring.
- Dose-response evaluations to determine the no-effect levels and potency of different compounds.
Main Results:
- Daunomycin, adriamycin, and other tested anthracyclines inhibited mitochondrial oxygen consumption and/or ATP production in vitro.
- In vivo, adriamycin and NSC-149584 decreased oxygen consumption, while daunomycin and other analogs primarily affected ATP production.
- Daunomycin and adriamycin were the most potent inhibitors, damaging mitochondrial function at cumulative doses around 10 mg/kg.
- ECG changes, including QRS widening, S-wave trough development, intraventricular block, bradycardia, and heart failure, correlated with mitochondrial impairment.
Conclusions:
- Anthracycline antibiotics directly impair rat heart mitochondrial function, impacting energy production pathways.
- The observed mitochondrial dysfunction is closely linked to the development of cardiotoxic effects, as evidenced by ECG abnormalities.
- These findings highlight mitochondrial damage as a key mechanism in anthracycline-induced cardiotoxicity, informing strategies for managing this adverse effect.