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目的在一定范围内激活β_2肾上腺素能受体(AR)可以在不加重心室重构的前提下改善心力衰竭(心衰)大鼠心功能,推测β_1AR 阻断剂联合β_2AR 激动剂有可能进一步改善心衰大鼠心功能并减轻心肌细胞凋亡,该实验对此进行了研究并探讨了其机制。方法随机选取9只雄性Wistar 大鼠为对照组。将异丙基肾上腺素诱导的心衰大鼠随机分为美托洛尔组(n=11),联合治疗组(n=11),安慰剂组(n=10)。美托洛尔组给予美托洛尔50 mg/kg,一日两次灌胃。联合治疗组给予非诺特罗125μg/kg,美托洛尔50 mg/kg 一日两次灌胃。安慰剂组给予等量生理盐水一日两次灌胃。对照组不予处理。治疗8周后应用超声心动图评价心功能,TUNEL 法检测心肌细胞凋亡指数,测定Caspase-3酶活性,Western blot 测定 bcl-2及 bax 蛋白质表达,测定脏器重量/体重,组织病理学测定胶原容积分数(CVF)。结果 (1)美托洛尔组及联合治疗组均较安慰剂组左室舒张末期直径(LVEDd)、左室收缩末期直径(LVESd)、E 峰 A 峰比值(E/A)明显下降,短轴缩短率(Fs)、射血分数(EF)则有明显增高。联合治疗组较美托洛尔组 LVEDd、LVESd 有进一步降低(均为 P<0.05),FS、EF 则有进一步增高(均为 P<0.01)。(2)美托洛尔组及联合治疗组较安慰剂组左室重量体重比(LVW/BW)、肺脏重量体重比(PW/BW)及 CVF 明显降低(均为 P<0.01)。联合治疗组 LVW/BW 及PW/BW 较美托洛尔组进一步降低(P<0.01),但两组之间 CVF 无显著差异。(3)美托洛尔组及联合治疗组较安慰剂组心肌细胞凋亡指数(AI)及 Caspase-3活性均有明显减低。联合治疗组较美托洛尔组有进一步减低(均为 P<0.01)。(4)与安慰剂组相比,美托洛尔组及联合治疗组 bax 蛋白表达有明显下降而 bcl-2/bax 显著升高,并且以联合治疗组改善更为显著(均为 P<0.01)。结论β_1AR 阻断剂联合β_2AR 激动剂较单用β_1AR 阻断剂进一步改善心衰大鼠的心功能,减轻心室重构。明显降低bax 蛋白表达及 bcl-2/bax,减轻心肌细胞凋亡很可能是其疗效提高的机制之一。
OBJECTIVE: Activation of β_2 adrenergic receptor (AR) in a certain range can improve cardiac function in rats with heart failure (heart failure) without aggravating ventricular remodeling. It is speculated that β_1AR blockers combined with β_2AR agonists may be further improved Heart failure in rats with heart failure and reduce myocardial apoptosis, the experimental study of this and explore its mechanism. Methods Nine male Wistar rats were randomly selected as the control group. Isoproterenol-induced heart failure rats were randomized to metoprolol (n = 11), combination therapy (n = 11) and placebo (n = 10). Metoprolol group was given Metoprolol 50 mg / kg twice a day. The combination treatment group was given fenoterol 125μg / kg, metoprolol 50 mg / kg orally twice daily. Placebo group given equal volume of saline twice daily gavage. Control group did not deal with. The heart function was evaluated by echocardiography after 8 weeks of treatment. The apoptosis index of cardiomyocytes was measured by TUNEL method. The activity of Caspase-3 was detected by Western blot. The expression of bcl-2 and bax protein was detected by Western blot. Collagen volume fraction (CVF). Results (1) The LVEDd, LVESd and E / A ratio of metoprolol group and combination group decreased significantly compared with placebo group Axial shortening rate (Fs), ejection fraction (EF) was significantly higher. Compared with metoprolol group, LVEDd and LVESd in combination therapy group were further decreased (all P <0.05), and FS and EF were further increased (all P <0.01). (2) The LVW / BW, PW / BW and CVF in the metoprolol group and the combination group were significantly lower than those in the placebo group (both P <0.01). The LVW / BW and PW / BW in the combined treatment group were lower than those in the metoprolol group (P <0.01), but there was no significant difference between the two groups. (3) The apoptosis index (AI) and Caspase-3 activity in metoprolol group and combination group were significantly lower than those in placebo group. Compared with metoprolol group, the combination therapy group further reduced (all P <0.01). (4) Compared with the placebo group, the expression of bax protein and the bcl-2 / bax protein in the metoprolol group and the combination group were significantly lower than those in the placebo group (P <0.01) ). Conclusion β_1AR blocker combined with β_2AR agonist can improve cardiac function and reduce ventricular remodeling in heart failure rats than β_1AR blocker alone. Obviously, the decrease of bax protein expression and bcl-2 / bax, and the decrease of cardiomyocyte apoptosis may be one of the mechanisms of its curative effect.