title: Bilirubin attenuates bufadienolide-induced ventricular arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated intracellular Na(+) levels.
abstract: Bufadienolides, known ligands of the sodium pump, have been shown to inhibit the proliferation of several cancer cell types. However, their development to date as anticancer agents has been impaired by a narrow therapeutic margin resulting from their potential to induce cardiotoxicity. In the present study, we examined the effects of bilirubin, an endogenous antioxidant, on the cardiotoxicity of bufadienolides (derived from toad venom) in guinea-pigs. The results showed that bufadienolides (8 mg/kg) caused ventricular arrhythmias, conduction block, cardiac dysfunction and death in guinea-pigs. Pretreatment with bilirubin (75 and 150 mg/kg) significantly prevented bufadienolide-induced premature ventricular complexes, ventricular tachycardia, ventricular fibrillation and death. Bilirubin also markedly improved the inhibition of cardiac contraction in bufadienolide-treated guinea-pigs as evidenced by increases in left ventricular systolic pressure and decreases in left ventricular diastolic pressure in vivo. Furthermore, bilirubin significantly reduced the intracellular sodium content ([Na(+)](                            i                         )) in ex vivo bufadienolide-stimulated guinea-pig ventricular myocytes loaded with the sodium indicator Sodium Green. An antitumor study showed that bilirubin did not compromise the ability of bufadienolides to inhibit gastric cancer cell MGC-803 proliferation. These results suggested that bilirubin can attenuate bufadienolide-induced arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated [Na(+)](                            i                         ) and may improve bufadienolide therapeutic index in cancer treatment.
authors: Jiangsu Key Laboratory for TCM Formulae Research, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors: Hongyue
authors: H
authors: Ma
authors: Junfeng
authors: J
authors: Zhang
authors: Jiejun
authors: J
authors: Jiang
authors: Jing
authors: J
authors: Zhou
authors: Huiqin
authors: H
authors: Xu
authors: Zhen
authors: Z
authors: Zhan
authors: Qinan
authors: Q
authors: Wu
authors: Jinao
authors: J
authors: Duan
mesh_terms: D000664:Amphibian Venoms / Q000633:toxicity; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D001663:Bilirubin / Q000494:pharmacology / Q000627:therapeutic use*; D002018:Bufanolides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002023:Bufo bufo; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004562:Electrocardiography / Q000379:methods; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D012964:Sodium / Q000378:metabolism*
chemical_list: D000664:Amphibian Venoms; D002018:Bufanolides; D002316:Cardiotonic Agents; C087925:bufadienolide; D012964:Sodium; D001663:Bilirubin