| Part 1 A Rat Model of Adriamycin Induced Chronic Congestive Heart FailureObjective: The purpose of the present study was to establish a effective rat model of adrimycin induced chronic congestion heart failure(CHF).Methods: Fourty-two adult male Wistar rats were randomly divided into 2 groups:CHF group(n=24) and normal control group(NC group,n=6);Adrimycin was injected to the CHF group rats by intraperitoneal at a dose of 2mg/kg per 3 days for 5 times,then at a dose of 2 mg/kg per 7 days for 5 times,the NC group rats was injected with 0.9% saline the same methods. Transthoracic Echocardiography was applied to evaluate rats heart function; The pathological change was analyzed by histological hematoxylin-eosin staining; electronmicroscope was applied to evaluate rats'morphology of myocardium;The blood plasma NE level was measured by liquid phase chromatography.Results: At the end of 10th week after administration of adriamycin, The pathological examination was consistent with histological changes of cardiomypathy;Compared to NC group,LV end–diastolic diameter(LVEDD) and LV end systolic diameter(LVESD) were significantly increased(0.58±.017 vs 0.45±0.05 and 0.23±0.03 vs 0.05±0.006,P<0.05和P<0.01), LV ejection fraction(LVEF) and LV fraction shortening(LVFS) were significantly decreased (72.4±2.77 vs 93.51±4.74和37.72±5.43 vs 62.21±7.62, all P<0.05) in CHF group 10 weeks after administration of adriamycin;The blood plasma level of NE was significantly higher in CHF group than in NC group (13.94±9.61 vs 61.52±21.44, P <0.01).Conclusions: Chronic administration of intraperitoneal injection adriamycin to rat results in left ventricular myocardial fibrosis and heart failure; A effective chronic congestion heart failure rat model induced by adrimycin was established. Part 2The effects of Carvedilol on adrenergic receptors expressions in rats'myocardium with heart failureObjectives:To investigate the alterations of the adrenergic receptors mRNA expressions in chronic heart failure (CHF) rats'myocardium after carvedilol administration.Methods:Fourty-two adult male Wistar rats were randomly divided into 2 groups:CHF group(n=36) and normal control group(NC group,n=10). Adrimycin was injected by intraperitoneal to the CHF group rats to establish a CHF study model.CHF group was randomly divided into 3 groups: CHF carvedilol administration group(CHF-C group,n=12),CHF metoprolol administration group (CHF-M group,n=12),CHF placebo administration group (CHF-P group,n=12); Carvedilol was administrated by intragastric to CHF-C group at a dose of 0.25mg/kg/d at the fifth week after adrimycin injection, Metoprolol was administrated by intragastric to CHF-M group at a dose of 0.25mg/kg/d at the fifth week after adrimycin injection, starch was administrated by intragastric to CHF-P group;α1A-,β1-,β2-,β3-Adrenergic receptors mRNA expressions in myocardial tissue were analyzed using the reverse transcriptase polymerase chain reaction(PCR).Results:⑴The expression ofα1A-AR mRNA in CHF-P group and CHF-M group rats'myocardium were significantly higher than those in NC group rats (0.55±0.16 vs 0.32±0.09 and 0.48±0.14 vs 0.32±0.09, P<0.05);There were no significant difference on the expression ofα1A-AR mRNA in rats'myocardium between NC group and CHF-C group(0.34±0.08 vs 0.32±0.09,P>0.05).⑵The expression ofβ1-AR mRNA in rats'myocardium was significantly decreased in CHF-P group and CHF-M group than that in NC group (0.68±0.18 vs 0.96±0.21 and 0.78±0.19 vs 0.96±0.21,P<0.01 and P<0.05); The expression ofβ1-AR mRNA in rats'myocardium was significantly higher in CHF-C group than that in CHF-P group (0.83±0.18 vs 0.68±0.18,P<0.05);There was no significant difference on the expression ofβ1-AR mRNA in rats'myocardium between CHF-C group and NC group(0.83±0.18 vs 0.96±0.21, P>0.05).⑶There were no significant difference on theβ1-AR mRNA in rats'myocardium among four groups.⑷The expression ofβ3-AR mRNA in rats'myocardium was significantly lower in CHF-C group than that in CHF-P group(0.30±0.09 vs 0.47±0.13,P<0.05); The expression ofβ3-AR mRNA in rats'myocardium was no significant difference in CHF-M group and in CHF-P group.⑸The ratios ofα1A/β1 andβ3/β1 in rats'myocardium in CHF-C group were more closely to those in NC group.Conclusions:⑴β1-Adrenoceptor mRNA expression was significantly decreased in heart failure rats'myocardium,α1A-andβ3-AR mRNA expressions was significantly increased in heart failure rats'myocardium;⑵Carvedilol treatment can upregulateβ1-adrenoceptor mRNA expression and downregulateα1A-andβ3-AR mRNA expressions in CHF rats'myocardium,and accordingly,normalize the ratios ofα1A/β1 andβ3/β1 in CHF rats'myocardium. Part 3Effects of Carvedilol on the Activity of Cardiac Sympathetic Nerve in Chronic Heart Failure RatsObjective: To investigated the effects of carvedilol on the expressions of nerve growth factor (NGF) and tyrosine hydroxylase (TH) in chronic heart failure (CHF) rats'myocardium.Methods:①Fourty-two adult male Wistar rats were randomly divided into 4 groups: CHF carvedilol administration group (CHF-C group, n=9), CHF metoprolol administration group (CHF-M group, n=9), CHF terazosin administration group (CHF-T group,n=9), CHF placebo administration group(CHF-P group, n=9) and normal control group(NC group, n=6);②Adrimycin was injected by intraperitoneal to the rats of CHF groups to establish a CHF study model;③Carvedilol was administrated by intragastric to CHF-C group rats at a dose of 0.25mg/kg/d at the fifth week after adrimycin injected,Metoprolol was administrated by intragastric to CHF-M group rats at a dose of 0.25mg/kg/d at the fifth week after adrimycin injected, starch was administrated by intragastric to CHF-P group rats at the same way;④NGF and TH mRNA expressions in myocardial tissue were analyzed using the reverse transcriptase polymerase chain reaction (PCR),NGF and TH protein expressions in myocardial tissue were analyzed by western blot.Results:⑴Compared to NC group, the expressions of NGF mRNA and protein in myocardium were significantly decreased in CHF-P group (0.69±0.17 vs 1.63±0.30 and 0.52±0.09 vs 1.10±0.29,all P<0.01);Compared to CHF-P group, the expressions of NGF mRNA and protein in myocardium were significantly increased in CHF-C group (1.01±0.28 vs 0.69±0.17 and 0.84±0.24 vs 0.52±0.09,all P<0.05); Compared to CHF-P group, the expressions of NGF mRNA and protein in myocardium were significantly increased in CHF-T group (0.94±0.23 vs 0.69±0.17 and 0.81±0.18 vs 0.52±0.09,all P<0.05); The expressions of NGF mRNA and protein in myocardium were no significant difference in CHF-M group and CHF-P group(0.77±0.20 vs 0.69±0.17 and 0.53±0.12 vs 0.52±0.09,all P>0.05);⑵The expressions of TH mRNA and protein in myocardium were significantly lower in CHF-P group than in NC group (0.94±0.28 vs 1.78±0.49 and 0.86±0.24 vs 1.42±0.41, all P<0.01); Compared to CHF-P group, the expressions of TH mRNA and protein in myocardium were significantly increased in CHF-C group (1.36±0.39 vs 0.94±0.28 and 1.10±0.37 vs 0.86±0.24,all P<0.05); Compared to CHF-P group, the expressions of TH mRNA and protein in myocardium were significantly increased in CHF-T group (1.19±0.0.30 vs 0.94±0.28 and 0.99±0.30 vs 0.86±0.24,all P<0.05); The expressions of TH mRNA and protein in myocardium were no significant difference in CHF-M group and CHF-P group(0.97±0.30 vs 0.94±0.28 and 0.90±0.31 vs 0.86±0.24,all P>0.05);⑶Blood plasma levels of NE in CHF-P group were significantly higher than NC group (61.76±21.03 vs 13.94±3.39, P<0.01);Blood plasma level of NE in CHF-C group were significantly lower than CHF-P group (46.14±9.91 vs 61.76±21.03, P<0.05); There was no significant difference of blood plasma level of NE between CHF-M group and CHF-C group.Conclusions: The expressions of NGF and TH were significantly decreased in heart failure rats'myocardium; Carvedilol prevents the decrease the expressions of NGF and TH in heart failure rats'myocardium; A low degree of alpha 1-adrenoceptor blockade in myocardium may contribute to the beneficial effects of carvedilol in heart failure.we presume that carvedilol conduce to improve the activity of cardiac sympathetic nerve in chronic heart failure cases.
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