Prominent cardioprotective effects of third generation beta blocker nebivolol against anthracycline-induced cardiotoxicity using the model of isolated perfused rat heart.
Nebivolol is a cardioselective beta-blocker (BB) currently used for the treatment of hypertension. It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other BBs. Carvedilol is a nonselective ss-adrenergic receptor antagonist that also blocks alpha1-adrenergic receptors and is a potent antioxidant. Anthracyclines (ANTs), daunorubicin and doxorubicin, are commonly used in the treatment of several tumours, but their cardiac toxicity prevents their use at maximum myelotoxic doses, representing an important problem. In this study, we have evaluated the role of these BBs administered in combination with ANTs (daunorubicin and doxorubicin) on a reduction in cardiac toxicity. The combination of BB and ANTs has reduced the release of GSSG and GSH; in particular, co-treatment with nebivolol to ANTs has shown a significant reduction. The total integrated creatine kinase and troponin T activities were improved by BB and ANTs co-treatment. A significant reduction of their release was observed when hearts were treated with nebivolol. Cardiac tissue activity of gluthatione reductase was not significant and similar among experimental groups. In contrast, gluthatione peroxidise, Mn-superoxide dismutase and nitrite/nitrate release were increased after co-treatment with nebivolol. Finally, three parameters have been used to evaluate the cardiac toxicity of ANTs: the left ventricular pressure developed under a constant perfusion pressure (LVDP), the rate of variation of this parameter during systole (contractility) (LV/dt)max and during diastole (relaxation) (LV(dP/dt)min. Combination with BB has shown a reduction in cardiac toxicity; in particular, nebivolol has exerted the most significant cardioprotective effect.
de Nigris
Filomena
F
Department of General Pathology, Division of Clinical Pathology, 1st School of Medicine and Surgery, II University of Naples, Complesso S. Andrea delle Dame, Via L. de Crecchio 7, 80138 Naples, Italy.
Rienzo
Monica
M
Schiano
Concetta
C
Fiorito
Carmela
C
Casamassimi
Amelia
A
Napoli
Claudio
C
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D001578:Benzopyrans / Q000008:administration & dosage*; D002227:Carbazoles / Q000008:administration & dosage; D000077261:Carvedilol; D003630:Daunorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004983:Ethanolamines / Q000008:administration & dosage*; D005978:Glutathione / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D000068577:Nebivolol; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress; D011412:Propanolamines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley
D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D001578:Benzopyrans; D002227:Carbazoles; D004338:Drug Combinations; D004983:Ethanolamines; D009566:Nitrates; D011412:Propanolamines; D000068577:Nebivolol; D000077261:Carvedilol; D005978:Glutathione; D003630:Daunorubicin