Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats.
Daunorubicin (DNR) is one of the anthracycline anti-tumor agents widely used in the treatment of acute myeloid leukemia. However, the clinical use of DNR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of carvedilol, a nonselective beta-blocker against DNR-induced cardiotoxicity and nephrotoxicity. Rats were treated with a cumulative dose of 9 mg/kg body weight DNR (i.v.). Carvedilol was administered orally every day for 6 weeks. DNR rats showed cardiac and nephrotoxicities as evidenced by worsening cardiac and kidney functions, which were evaluated by hemodynamic and echocardiographic studies, and by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdeyde level and the total level of glutathione peroxidase activity in both heart and kidney tissues. These changes were reversed by treatment with carvedilol, which resulted in significant improvement in the cardio-renal function. Furthermore, carvedilol down-regulated matrix metalloproteinase-2 expression in the heart, increased nephrin expression in the kidney, and attenuated the increased protein expression of NADPH oxidase subunits in heart and kidney. Moreover, carvedilol reduced myocardial and renal apoptosis and improved the histopathological changes in heart and kidney induced by DNR. In conclusion, the present study demonstrated a beneficial effect of carvedilol treatment in the prevention of DNR-induced cardiotoxicity and nephrotoxicity by reversing the oxidative stress and apoptosis.
Arozal
Wawaimuli
W
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima Akiha-ku, Niigata City 956-8603, Japan.
Watanabe
Kenichi
K
Veeraveedu
Punniyakoti T
PT
Ma
Meilei
M
Thandavarayan
Rajarajan A
RA
Sukumaran
Vijayakumar
V
Suzuki
Kenji
K
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles; D000077261:Carvedilol; D003404:Creatinine / Q000378:metabolism / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D006321:Heart; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011412:Propanolamines; D051381:Rats; D017207:Rats, Sprague-Dawley
D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D003404:Creatinine; D020778:Matrix Metalloproteinase 2; D003630:Daunorubicin