White M, Roden R, Minobe W, Khan M F, Larrabee P, Wollmering M, Port J D, Anderson F, Campbell D, Feldman A M
Division of Cardiology, University of Utah Medical Center, Salt Lake City.
Circulation. 1994 Sep;90(3):1225-38. doi: 10.1161/01.cir.90.3.1225.
Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts.
Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts.
There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.
在模型系统和人类体内，衰老会降低心脏β-肾上腺素能反应性。本研究的目的是全面评估非衰竭人类心脏中β受体-G蛋白-腺苷酸环化酶复合物的年龄相关变化。
从器官捐献者处获取26颗年龄在1至71岁之间的非衰竭离体人类心脏，并对β-肾上腺素能神经效应系统进行药理学研究。当将研究对象分为年龄最小的13名和年龄最大的13名受试者时，通过最大[125I]ICYP结合（βmax）评估的总β受体密度在老年心脏的左心室中降低了37%，右心室中降低了31%（均P<.05），且这种下调仅限于β1亚型（左心室β1密度与供体年龄的r=.78）。老年供体心脏的ICYP-异丙肾上腺素（ISO）竞争曲线向右移动3至4倍，并且在高亲和力激动剂结合状态下的受体减少43%（P<.05）。老年心脏对ISO、齐帕特罗（β2激动剂）以及G蛋白敏感探针福斯可林、Gpp(NH)p和NaF的腺苷酸环化酶刺激作用降低。相比之下，对锰（腺苷酸环化酶催化亚基的特异性激活剂）的反应没有变化。对老年和年轻心脏制备的膜进行毒素催化的ADP核糖基化显示，霍乱毒素（Gs）处理后降低了29%至30%（P<.05），但百日咳毒素（Gi）处理后无差异。相对于年轻供体心脏，老年供体心脏中分离的右心室小梁对ISO的收缩反应降低了46%，ISO的EC50增加了10倍。
随着年龄增长，心脏β-肾上腺素能反应性显著降低。这是通过多种机制发生的，包括β1受体的下调和激动剂结合减少、β2受体的解偶联以及异常的G蛋白介导的信号转导。
