Study Of The Effects And Mechanisms Of Carvedilol In SD Rat With Adriamycin-induced Dilated Cardiomyopathy

Objective: To evaluate the protective effects of carvedilol to cardiac function in SD rats with adriamycin-induced dilated cardiomyopathy (DCM), and explore its possible mechanisms by influencing the capability of oxidative stress and the expression of related apoptosis genes.Methods: To build adriamycin-induced dilated cardiomyopathy rat models with administered adriamycin intraperitoneally injected (2mg/kg weekly, general 8 weeks, total doses 16mg/kg). Randomly divided into three groups (n=10 in each group): carvedilol group (60mg/kg daily), DCM group (give an equivalent volume of 0.9% saline daily), and control group (give an equivalent volume of 0.9% saline daily), total 8 weeks. AT 9^th week of remedy, the left ventricular dimension at end-diastole (LVDD) and ejection fraction (LVEF) were measured with echocardiography; maximum left ventricular developed pressure increase rate (+LVdp/dt_max) and decrease rate (-LVdp/dt_min) were recorded with continuous physiological monitors; the serum oxidative stress including total antioxidation capacity (T-AOC) and malondialdehyde (MDA) were studied. And then executed the rats, obtained the LV relative weight (LVRW). The Fas, FasL, Bcl-2 and Bax mRNA and proteins in cardiac muscle respectively were determined by methods of RT-PCR and Western blot. Histopathological study was done by HE and VG dyeing. Collagen volume fraction (CVF) was calculated.Results:(1) Compared with normal groups, LVDD (P<0.01) was significantly increased and LVEF (P<0.01) reduced in adriamycin-induced cardiomyopathy rat models. Those were similar to dilated cardiomyopathy.(2) Cardiac function:①echocardiography, compared with CON group, DCM group LVDd was significantly increased[(7.19±0.28)mm vs (5.59±0.29)mm, (P<0.01)], and carvedilol group(6.79±0.29)mm decreased greatly, (P<0.01); Compared with CON group, DCM group LVEF was significantly decreased[(78.85±1.04)% vs (89.68±1.08)%, (P<0.01)], while carvedilol group(85.17±1.61)% increased greatly, (P<0.01).②hemodynamic parameters, compared with CON group, DCM group LVSP was lower greatly[(103.8±6.9)mmHg vs (121.8±1.8)mmHg, (P<0.01)], and carvedilol group(130.8±2.8)mmHg was higher greatly, (P<0.01); Compared with CON group, DCM group±dp/dt_max were significantly decreased, [(2337.7±447.9)mmHg.s^-1 vs (6630.4±296.5)mmHg.s^-1, (P<0.01)] and [(2238.5±296.5)mmHg.s^-1 vs(5560.8±122.1)mmHg.s^-1, (P<0.01)], while carvedilol group +dp/dt_max(5002.1±473.4)mmHg.s^-1, -dp/dt_max (3382.3±222.2)mmHg.s^-1 increased greatly, (P<0.01); Compared with CON group, DCM group LVEDP was significantly increased [(23.4±9.1)mmHg vs (6.5±0.6)mmHg, (P<0.01)] , and carvedilol group(4.72±0.8)mmHg decreased greatly, (P<0.01).(3) Oxidative stress: Compared with CON group, DCM group could significantly decrease the activity of T-AOC, [(3.00±0.66)U/ml vs (9.11±1.45)U/ml, P<0.01] and improve the contents of MDA greatly, [(8.89±1.64)nmol/ml vs (4.32±0.87)nmol/ml, P<0.01]; while, in carvedilol group, the activity of T-AOC (5.54±0.99)U/ml was enhanced significantly, (P<0.01), and the contents of MDA (6.39±1.02)nmol/ml was decreased (P<0.05).(4) Related apoptosis genes:①RT-PCR, compared with CON group, in DCM group, the mRNA of Bax, Fas, FasL expression were much higher[(0.88±0.09) vs (0.32±0.11), P<0.05], [(0.85±0.07) vs (0.64±0.14), P<0.05], [(0.67±0.11) vs (0.44±0.13), P<0.05], and the mRNA of Bcl-2 expression was much lower than CON group[(0.45±0.05) vs (0.78±0.12), P<0.05]; while, in carvedilol group, the mRNA of Bax(0.65±0.12), Fas(0.72±0.10) expression were much lower, (P<0.05), and the mRNA of Bcl-2(0.64±0.08) was much higher, (P<0.05), while the FasL expression was no significant difference between DCM group and carvedilol group.②Western, At the same time, compared with CON group, the protein of Fas, FasL expression were much higher in DCM group [(0.47±0.14) vs (0.12±0.05), P<0.05], [(0.37±0.07) vs (0.17±0.04), P<0.05]; and in carvedilol group, only the protein of Fas expression(0.29±0.11) was much lower than DCM group, (P<0.05), As the protein of FasL expression(0.36±0.09), there were no significant difference between DCM group and carvedilol group,(P>0.05).(5) Cardiac histopathological characteristics:①Collagen volume fraction(CVF), compared with CON group, in DCM group, the CVF improved significantly [(0.138±0.011) vs (0.021±0.005), P<0.01]; While carvedilol group (0.072±0.013) was better (P<0.01).②LV relative weight (LVRW), compared with CON group, in DCM group, the LVRW increased significantly, (P<0.01), and carvedilol group (1.86±0.08) was decreased greatly, (P<0.01).Conclusion: Carvedilol can relieve adriamycin-induced hemodynamic abnormality mainly, improve cardiac systolic and diastolic function greatly and reverse ventricular remodeling by improving the ability of oxidative stress, inhibitting the expression of related apoptosis genes, eventually play an importan role in heart protection.