Effects Of Carvedilol On Ventricular Arrhythmias In Rabbits With Adriamycin Cardiomyopathy

Objections:To investigate the effects of oxidative stress on cardiac structure and electrical stability in rabbits with adriamycin cardiomyopathy, and explore the relationship between oxidative stress and adriamycin cardiomyopathy. To investigate the effects of carvedilol on ventricular arrhythmias and the expression of ryanodine receptors2in rabbits with adriamycin cardiomyopathy and discuss mechanism of ventricular arrhythmias.Methods:Japanese white rabbits were randomly divided into four groups:the control group, the adriamycin group, the metoprolol group and the carvedilol group. Rabbits in the adriamycin group, the metoprolol group and the carvedilol group were intravenously injected at auri-edge with adriamycin hydrochloride (1mg.kg-1) twice a week for8weeks, and the control group was injected with equal volumn of saline at the same timepoint.3weeks later, rabbits in the metoprolol group and the carvedilol group were intragastric administration with metoprolol and carvedilol (Smg.kg-1.d-1) respectively, and those in the control group and the adriamycin group were intragastric administration with equal volume of saline.1)2months later, left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiogram, and plasma levels of amino terminal-pro brain natriuretic peptide (NT-proBNP), superoxide dismutase(SOD) and malondialdehyde(MAD) were measured.2) The wedge preparations from the rabbit heart were perfused with Tyrode's solution, volume electrocardiogram, QT interval, transmural repolarization dispersion (TDR) and the incidences of triggered activity and ventricular arrhythmias were recorded.3) By enzymatic dissociation method single ventricular myocytes were isolated, then ction potentials (APs) were recorded by whole cell patch clamp technique. The incidences of delayed afterdepolarizations (DADs) and triggered activity (TA) were monitored under fast frequency electrical stimulation.4) The ryanodine receptor2and SERCA2a were measured by Western blotting.Results1) Compared the control group, adriamycin significantly increased serum MDA, NT-proBNP and LVEDd, and decreased SOD and LVEF.(P<0.05). There was no significant difference in MDA, NT-proBNP, SOD, LVEF and LVEDd between the adriamycin group and the metoprolol group. Carvedilol markedly increased serum MDA and LVEF, decreased SOD, TNP and LVEDd compared with adriamycin group (P<0.05)2) No triggered activity and ventricular arrhythmias was induced in control group. The incidences of triggered activity and ventricular arrhythmias occurred in10/10and9/10rabbits in adriamycin group, in9/10and7/10rabbits in the metoprolol group, and in4/10and2/10rabbits in the carvedilol group respectively. The incidences of triggered activity and ventricular arrhythmias in the adriamycin group were significantly higher than those in the control group. However, the incidences were significantly lower in the carvedilol group when compared with those in the adriamycin group.3) Compared with the control group, single cell action potential duration (APD) was prolonged, RyR2and SERCA2a protein expression were reduced, the incidences of DADs and TA were obviously increased in the adriamycin group (P<0.05). There was no difference of APD, RyR2and SERCA2A protein expression level, and the incidences of DADs and TA between the adriamycin group and the metoprolol group. Compared with the adriamycin group, carvedilol can short APD, increase protein expression level of RyR2and SERCA2a and decrease the incidences of DADs and TA (P<0.05)Conclusions:Oxidative stress was increased, and heart structure and function was significantly impaired in the adriamycin group. Carvedilol can improve abnormal cardiac structure and inhibit ventricular arrhythmias in rabbit with adriamycin cardiomyopathy. Carvedilol can inhibit ventricular tachycardia in rabbit with adriamycin cardiomyopathy and protect adriamycin-induced cardiotoxicity through decreasing oxygen free radial production, which is related to dysfunction of RyR2.