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Role of high affinity β-adrenergic receptor, β-arrestin, and β-adrenergic receptor kinase during the development of heart failure

高亲和力β-肾上腺素受体、β-抑制素和β-肾上腺素受体激酶在心力衰竭发生过程中的作用

基本信息

批准号：
12670700
负责人：
YAMAMOTO Takeshi
金额：
$ 2.05万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

To examine the function of intracellular β-adrenergic receptor signal pathway during the development of pacing-induced heart failure, hemodynamic measurements were made with nine mongrel dogs fully awake. Signaling components were also measured using a crude cardiac sarcolemmal preparation. Furthermore, we assessed the relationship between the physiologic hemodynamic parameters and the biochemical components. Three dogs were paced for 1 d, two dogs were paced for 1 wk, and two dogs were paced for 6-7 wk. The data from dogs after 1 d, 1 wk, and 6-7 wk of pacing were compared with two sham-operated dogs. Left ventricular dP/dt in response to the acute challenges to isoproterenol was significantly decreased at 1 d and was depressed further at 1 and 6-7 wk of pacing. Both the fraction of β-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased after 1 d of pacing. Ryanodine receptor decreased after 1 d of pacing, but not depressed furthermore. There were no significant changes in the total β-adrenergic receptor density, and the functional activity of Gs. β-adrenergic receptor kinase and β-arrestin did not estimated because of technical failure. Blunt responsiveness to isoproterenol derived mainly from the loss of high affinity cardiac β-adrenergic receptors. High affinity β-adrenergic receptor appears to be the most crucial change in the physiological deteriorations during the initial development of heart failure.

为探讨细胞内β-肾上腺素能受体信号通路在起搏性心力衰竭发生发展过程中的作用，对9只完全清醒的杂种犬进行了血流动力学测定。还使用粗心脏肌膜制备物测量信号组分。此外，我们评估了生理血流动力学参数和生化成分之间的关系。3只犬起搏1 d，2只犬起搏1 wk，2只犬起搏6-7 wk。将起搏后1 d、1 wk和6-7 wk的数据与2只假手术犬进行比较。左心室对异丙肾上腺素急性刺激的dP/dt在起搏后1d显著降低，并在起搏后1周和6-7 wk进一步降低。起搏1d后，高亲和力β受体结合激动剂的比例和腺苷酸环化酶活性均降低。起搏1d后Ryanodine受体下降，但未进一步降低。总β-肾上腺素能受体密度和Gs功能活性无显著变化。β-肾上腺素能受体激酶和β-arrestin因技术故障未进行检测。对异丙肾上腺素的钝性反应主要来源于高亲和力心脏β-肾上腺素能受体的丧失。高亲和力β-肾上腺素能受体似乎是心力衰竭早期生理恶化中最关键的变化。