Ahmet Ismayil, Krawczyk Melissa, Heller Phillip, Moon Chanil, Lakatta Edward G, Talan Mark I
Gerontology Research Center, Baltimore, MD 21224, USA.
Circulation. 2004 Aug 31;110(9):1083-90. doi: 10.1161/01.CIR.0000139844.15045.F9. Epub 2004 Aug 16.
Studies in isolated cardiac myocytes have demonstrated that signaling via specific beta1-adrenergic receptor subtypes (beta1ARs) promotes but that signaling via beta2ARs protects from cell death. We hypothesized that prolonged beta(2)AR stimulation or beta1AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure.
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 beta2AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The beta1AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the beta2AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by beta2AR agonists than by the beta1AR blocker. Both beta2AR agonists and the beta1AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the beta2AR agonists reduced the Eed and the MI size by reducing infarct expansion.
These results provide proof of concept for the efficacy of chronic beta2AR stimulation in this DCM model.
对分离的心肌细胞的研究表明，通过特定的β1-肾上腺素能受体亚型（β1ARs）进行信号传导可促进细胞死亡，而通过β2ARs进行信号传导则可保护细胞免于死亡。我们推测，长期刺激β2AR或阻断β1AR均可保护心肌细胞免于死亡，从而改善慢性心力衰竭中的心脏重塑。
通过冠状动脉结扎在大鼠中诱导的大面积心肌梗死（MI）导致扩张型心肌病（DCM），其特征为梗死灶扩大和左心室（LV）舒张末期容积逐渐增加，同时射血分数（EF）降低，这通过反复超声心动图评估得出。结扎后8周的压力-容积分析显示，舒张期僵硬度（Eed）和动脉弹性（Ea）增加，收缩末期弹性（Ees）降低，且房室（AV）耦合（Ea/Ees）恶化。梗死周边和远隔心肌均存在细胞凋亡。在心肌梗死后2周开始慢性（6周）给予β2AR激动剂非诺特罗或齐特罗，可减少左心室扩张、梗死灶扩大的程度以及EF的下降。β1AR阻滞剂美托洛尔对前者无影响，且对EF的保护程度低于β2AR激动剂。结扎后8周，所有药物均减少了细胞凋亡，但β2AR激动剂的作用程度大于β1AR阻滞剂。β2AR激动剂和β1AR阻滞剂均改善了AV耦合，前者主要通过降低Ea，后者主要通过增加Ees。只有β2AR激动剂通过减少梗死灶扩大降低了Eed和心肌梗死面积。
这些结果为在该扩张型心肌病模型中慢性刺激β2AR的疗效提供了概念验证。
