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

为了研究细胞内β-肾上腺素能受体信号通路在起搏性心力衰竭发生过程中的作用，我们对9只完全清醒的杂种狗进行了血流动力学测量。信号成分也测量使用粗心脏肌基质制剂。此外，我们评估了生理血流动力学参数与生化成分之间的关系。3只狗1 d， 2只狗1周，2只狗6-7周。将2只假手术犬在起搏1 d、1周和6-7周的数据进行比较。左心室dP/dt对异丙肾上腺素急性刺激的反应在第1天显著降低，并在起搏1周和6-7周进一步降低。高亲和力β-肾上腺素能受体结合激动剂的比例和腺苷酸环化酶活性均在起搏1 d后下降。起搏1 d后，Ryanodine受体下降，但未进一步降低。β-肾上腺素能受体总密度和Gs的功能活性无显著变化。由于技术故障，没有对β-肾上腺素受体激酶和β-阻滞素进行估计。对异丙肾上腺素的钝性反应主要源于高亲和力心脏β-肾上腺素能受体的丧失。高亲和β-肾上腺素能受体的变化是心衰初期生理功能恶化的关键。

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.