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The isolated mouse atria as a new model for testing cardioactive drugs with special reference to doxorubicin
K Hermansen1, I M Rasmussen, H S Schou
1Department of Biological Sciences, Pharmacology and Toxicology, Royal Danish School of Pharmacy, Copenhagen O, Denmark.
Abstract:
Spontaneously beating isolated atria from mice were used as a new in vitro model to characterize the mechanism of the cardiotoxic action of the anthracycline cytostatic doxorubicin (Adriamycin). After stabilization at 28 degrees the atria showed a contractile rate and--force of 284 +/- 31 (S.D.) beats/min. and 49 +/- 6.5 mg. Doxorubicin (Dox) (10(-6)-10(-5) M) had a positive chronotropic action per se and decreased the pD2 for the chronotropic action of isoprenaline in a dose-dependent way. However only the effect of the higher concentration proved statistically significant, a concentration which also caused a marked decrease (63%) of the Emax. Pretreatment with Dox 15 mg/kg intraperitoneally 72 hr previously did not influence the pD2 but caused a significant increase in the Emax of the isoprenaline concentration response curve. The results indicate that Dox in vitro interferes with the beta-adrenoceptor function of isolated mouse atria in an unspecific way and that the subacute cardiotoxicity of Dox in mice is probably not due to interference with the beta-adrenoceptor system. Further it is concluded that isolated atria from mice may be a useful model for testing cardioactive drugs.
Insights
This study used isolated mouse atria to investigate doxorubicin cardiotoxicity. Doxorubicin interferes with beta-adrenoceptor function in vitro, but subacute cardiotoxicity in mice may not involve this system.
Area of Science:
- Pharmacology
- Cardiology
- Toxicology
Background:
- Doxorubicin (Adriamycin) is an anthracycline chemotherapeutic agent with known cardiotoxic effects.
- Understanding the mechanisms of doxorubicin-induced cardiotoxicity is crucial for patient management and drug development.
Purpose of the Study:
- To characterize the mechanism of doxorubicin's cardiotoxic action using an in vitro model of isolated mouse atria.
- To investigate the in vitro effects of doxorubicin on beta-adrenoceptor function and isoprenaline response.
- To evaluate if subacute cardiotoxicity in mice involves interference with the beta-adrenoceptor system.
Main Methods:
- Isolated spontaneously beating mouse atria were stabilized at 28°C.
- Doxorubicin (Dox) was applied in vitro at concentrations of 10⁻⁶–10⁻⁵ M.
- The chronotropic and inotropic effects of doxorubicin and isoprenaline were measured.
- Mice were pretreated with doxorubicin (15 mg/kg intraperitoneally) 72 hours prior to atrial isolation.
Main Results:
- In vitro, doxorubicin exhibited a positive chronotropic effect and decreased the pD2 for isoprenaline's chronotropic action in a dose-dependent manner.
- Higher doxorubicin concentrations significantly decreased isoprenaline's Emax (maximal effect) by 63%.
- In vivo pretreatment with doxorubicin did not alter isoprenaline's pD2 but significantly increased Emax, suggesting a complex interaction.
Conclusions:
- Doxorubicin interferes with beta-adrenoceptor function in isolated mouse atria in an unspecific manner in vitro.
- Subacute cardiotoxicity of doxorubicin in mice is unlikely to be solely due to interference with the beta-adrenoceptor system.
- Isolated mouse atria represent a potentially useful in vitro model for evaluating cardioactive drugs and their toxicological profiles.