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Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan
Department of Pharmacology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah Jakarta, State Islamic University, South Jakarta 15412, Indonesia
Department of Pharmacology, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia
Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 8 February 2011; in revised form: 23 February 2011 / Accepted: 10 March 2011 / Published: 17 March 2011
Abstract: Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as an anti-inflammatory drug. This study was designed to evaluate whether carvedilol exerts a protective role against inflammation-mediated cardiotoxicity in the daunorubicin (DNR)-induced rats. Carvedilol was administered orally to the rats every day for 6 weeks at a cumulative dose of 9 mg/kg body weight DNR. DNR significantly induced cardiac damage and worsened cardiac function as well as increased cardiac mast cell density, elevating the myocardial protein and mRNA expression levels of tumor necrosis factor-α, vascular cell adhesion molecule-1, inter-cellular adhesion molecule-1, nuclear factor kappa-B, cyclooxygenase-2, monocyte chemotactic protein -1 and interleukin -6 compared to that in the control group. Cotreatment with carvedilol significantly attenuated the myocardial protein and mRNA expression levels of these inflammatory markers, decreased cardiac mast cell density, improved histological cardiac damage and cardiac functions. In conclusion, inflammation plays a significant role in DNR-induced cardiotoxicity, and carvedilol contributes to cardioprotection against inflammation-mediated cardiotoxicity in DNR-induced rats through its anti-inflammatory mechanism.
Keywords: daunorubicin; carvedilol; inflammation; fibrosis
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Sari, F.R.; Arozal, W.; Watanabe, K.; Harima, M.; Veeravedu, P.T.; Thandavarayan, R.A.; Suzuki, K.; Arumugam, S.; Soetikno, V.; Kodama, M. Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats. Pharmaceuticals 2011, 4, 551-566.
Sari FR, Arozal W, Watanabe K, Harima M, Veeravedu PT, Thandavarayan RA, Suzuki K, Arumugam S, Soetikno V, Kodama M. Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats. Pharmaceuticals. 2011; 4(3):551-566.
Sari, Flori R.; Arozal, Wawaimuli; Watanabe, Kenichi; Harima, Meilei; Veeravedu, Punniyakoti T.; Thandavarayan, Rajarajan A.; Suzuki, Kenji; Arumugam, Somasundaram; Soetikno, Vivian; Kodama, Makoto. 2011. "Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats." Pharmaceuticals 4, no. 3: 551-566.