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Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release
Abstract:
We tested the hypothesis that cardiac histamine release mediates subacute doxorubicin (DXR) cardiotoxicity in rabbits. New Zealand white rabbits given DXR 20 mg/kg i.v. over 30 min developed myocardial damage 24 h later that was similar to that observed in humans. In isolated heart preparations, DXR produced dose-related cardiac histamine release at DXR concentrations of 1, 5, and 25 micrograms/ml given as 1-min exposures. Prior exposure of isolated hearts to 10 microM cromolyn sodium completely prevented histamine release from 5 micrograms/ml DXR. Pretreatment of animals with cromolyn produced significant protection against DXR-mediated subacute cardiotoxicity. We conclude that the release of cardiac histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.
Insights
Cardiac histamine release may contribute to doxorubicin (DXR) cardiotoxicity. Preventing histamine release with cromolyn sodium protected rabbits from DXR-induced heart damage, suggesting a therapeutic target.
Area of Science:
- Cardiology
- Pharmacology
- Toxicology
Background:
- Doxorubicin (DXR) is a widely used chemotherapy agent.
- Subacute cardiotoxicity is a significant concern with DXR treatment.
- The precise mechanisms underlying DXR cardiotoxicity are not fully understood.
Purpose of the Study:
- To investigate the role of cardiac histamine release in mediating subacute doxorubicin (DXR) cardiotoxicity.
- To determine if blocking histamine release can prevent DXR-induced myocardial damage.
Main Methods:
- New Zealand white rabbits were administered DXR intravenously.
- Myocardial damage was assessed 24 hours post-administration.
- Isolated rabbit heart preparations were used to study DXR-induced histamine release.
- The effect of cromolyn sodium on DXR-induced histamine release and cardiotoxicity was evaluated.
Main Results:
- DXR administration in rabbits caused myocardial damage similar to that seen in humans.
- DXR induced dose-related cardiac histamine release in isolated heart preparations.
- Cromolyn sodium pretreatment prevented DXR-induced histamine release.
- Cromolyn sodium pretreatment offered significant protection against DXR cardiotoxicity in vivo.
Conclusions:
- Cardiac histamine release is implicated in the pathogenesis of subacute doxorubicin cardiotoxicity.
- Targeting histamine release may represent a novel strategy to mitigate anthracycline-induced heart damage.