Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy
Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy
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DOI：
10.1161/01.cir.0000139844.15045.f9
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发表时间：
2004-08-31
期刊：
影响因子：
37.8
通讯作者：
Talan, MI
中科院分区：
文献类型：
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作者：
Ahmet, I;Krawczyk, M;Talan, MI
背景：对分离心肌细胞的研究表明，通过特定的β(1)-肾上腺素能受体亚型（β (1)ARs）的信号传导促进细胞死亡，但通过β (2)ARs的信号传导保护细胞死亡。我们假设延长β (2)AR刺激或β (1)AR阻断均可保护心肌细胞免于死亡，从而改善慢性心力衰竭患者的心脏重塑。方法和结果：经反复超声心动图评估，冠状动脉结扎引起的大鼠大面积心肌梗死（MI）导致扩张性心肌病（DCM），其特征是梗死扩张和左室舒张末期容积进行性增加，并伴有射血分数（EF）降低。结扎后8周的压力-容积分析显示，舒张刚度（Eed）和动脉弹性（Ea）升高，收缩期末期弹性（Ees）降低，动室耦合（Ea/Ees）恶化。梗死周围和远端心肌均存在细胞凋亡。慢性（6周）给予β (2)AR激动剂非诺特罗或辛特罗，在心肌梗死后2周开始，降低左室扩张程度，梗死扩张和EF下降。β (1)AR阻滞剂美托洛尔对前者没有影响，与β (2)AR激动剂相比，它对EF的保护程度更小。结扎后8周，所有药物均可减少细胞凋亡，但β (2)AR激动剂比β (1)AR阻滞剂减少的程度更大。β (2)AR激动剂和β (1)AR阻滞剂均能改善AV偶联，前者主要通过降低Ea，后者主要通过增加Ees。只有β (2)AR激动剂通过减少梗死扩张来降低ed和心肌梗死大小。结论：这些结果为慢性β (2)AR刺激在DCM模型中的有效性提供了概念证明。
Background-Studies in isolated cardiac myocytes have demonstrated that signaling via specific beta(1)-adrenergic receptor subtypes (beta(1)ARs) promotes but that signaling via beta(2)ARs protects from cell death. We hypothesized that prolonged beta(2)AR stimulation or beta(1)AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure.Methods and Results-A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the beta(2)AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The beta(1)AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the beta(2)AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by beta(2)AR agonists than by the beta(1)AR blocker. Both beta(2)AR agonists and the beta(1)AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the beta(2)AR agonists reduced the Eed and the MI size by reducing infarct expansion.Conclusions-These results provide proof of concept for the efficacy of chronic beta(2)AR stimulation in this DCM model.