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Antimuscarinic action of doxorubicin does not involve free-radical formation in isolated guinea pig hearts

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It has been proposed that the cardiotoxicity of anthracycline anticancer drugs involves free-radical formation. One early manifestation of toxicity appears to be caused by the antimuscarinic actions of these drugs. Accordingly, we examined whether the antimuscarinic action of one of these drugs, doxorubicin, is altered by antioxidants. In electrically stimulated left atrial muscle preparations obtained from guinea pig hearts, doxorubicin significantly increased the tissue concentration of thiobarbituric acid-reactive substance indicating increased lipid peroxidation. This effect of doxorubicin was significantly suppressed by the antioxidants α-tocopherol, dexrazoxane, and epigallocatechin gallate. Carbachol produced a concentration-dependent negative inotropic effect in our atrial preparations. Doxorubicin caused a seemingly parallel rightward shift of the concentration-response curve for carbachol. Neither α-tocopherol, dexrazoxane, nor epigallocatechin gallate reversed this effect of doxorubicin. The results indicate that in extirpated heart tissue, doxorubicin causes lipid peroxidation through the formation of free radicals. However, this effect of doxorubicin is unrelated to its antimuscarinic action.

Des données laissent croire que la cardiotoxicité des médicaments anticancéreux anthracyclines implique la formation de radicaux libres. Une manifestation précoce de la toxicité serait liée aux actions anti-muscariniques de ces médicaments. Nous avons donc examiné si les antioxydants modifient l’action anti-muscarinique de l’un de ces médicaments, la doxorubicine. Dans des préparations d’oreillette gauche de cobayes stimulée électriquement, la doxorubicine a augmenté de manière significative la concentration tissulaire d’une substance réagissant avec l’acide thiobarbiturique, ce qui indique une augmentation de la peroxydation lipidique. Cet effet a été diminué de manière significative par les antioxydants α-tocophérol, dexrazoxane ou épigallocatéchine gallate. Le carbachol a provoqué un effet inotrope négatif dépendant de la concentration dans les préparations. La doxorubicine a causé un déplacement en apparence parallèle de la courbe concentration-réponse au carbachol. Ni l’α-tocophérol, ni le dexrazoxane, ni l’épigallocatéchine gallate n’ont renversé l’effet de la doxorubicine. Les résultats indiquent que, dans le tissu cardiaque prélevé, la doxorubicine a causé une peroxydation lipidique par la formation de radicaux libres. Toutefois, cet effet n’est pas lié à son action anti-muscarinique.

Document Type: Research Article

Publication date: 2010-01-01

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  • Published since 1929, this monthly journal reports current research in all aspects of physiology, nutrition, pharmacology, and toxicology, contributed by recognized experts and scientists. It publishes symposium reviews and award lectures and occasionally dedicates entire issues or portions of issues to subjects of special interest to its international readership.
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