Yasunaga S, Yonemochi H, Saikawa T, Sakata T
First Department of Internal Medicine, School of Medicine, Oita, 879-5593, Japan.
J Mol Cell Cardiol. 2000 Jan;32(1):153-9. doi: 10.1006/jmcc.1999.1059.
The aim of this study was to elucidate the role of bradykinin in mediating captopril-induced upregulation of beta-adrenergic receptor (beta-AR). The density of beta-AR on the surface of cardiac myocytes was measured by binding assay using [(3)H]CGP-12177. Treatment of cultured neonatal rat cardiomyocytes with captopril resulted in a time-dependent elevation of bradykinin concentration in the culture medium. The increased bradykinin concentration was significant at 2, 3 and 6 h, but not at 12 h after exposure to captopril. This time-dependent effect of captopril on enhancement of bradykinin levels paralleled that of beta-AR upregulation. Exogenously applied bradykinin increased beta-AR density by 22, 30 and 35% at 0.01, 0.1 and 1 microm concentrations, respectively. Myocytes treated with 1 microm bradykinin responded to isoproterenol (ISP) in a dose-dependent manner, as demonstrated by acceleration of spontaneous beating frequency. These beating acceleration effects of bradykinin were abolished by Hoe 140. Stimulation of bradykinin B2 receptor by exogenously added bradykinin for 6 h was sufficient to produce beta-AR up-regulation to a level similar to that seen after 24 h. Our results indicate that bradykinin potentiation by ACE inhibitors regulates, at least in part, captopril-induced beta-AR up-regulation.
本研究的目的是阐明缓激肽在介导卡托普利诱导的β-肾上腺素能受体（β-AR）上调中的作用。使用[³H]CGP-12177通过结合试验测量心肌细胞表面β-AR的密度。用卡托普利处理培养的新生大鼠心肌细胞导致培养基中缓激肽浓度呈时间依赖性升高。在暴露于卡托普利后2、3和6小时，缓激肽浓度升高显著，但在12小时时不显著。卡托普利对缓激肽水平增强的这种时间依赖性效应与β-AR上调的效应平行。外源性应用缓激肽在0.01、0.1和1微摩尔浓度下分别使β-AR密度增加22%、30%和35%。用1微摩尔缓激肽处理的心肌细胞对异丙肾上腺素（ISP）呈剂量依赖性反应，表现为自发搏动频率加快。缓激肽的这些搏动加速作用被Hoe 140消除。外源性添加缓激肽刺激缓激肽B2受体6小时足以使β-AR上调至与24小时后相似的水平。我们的结果表明，ACE抑制剂增强缓激肽至少部分调节了卡托普利诱导的β-AR上调。
