Tavernier Geneviève, Toumaniantz Gilles, Erfanian Mortéza, Heymann Marie France, Laurent Karine, Langin Dominique, Gauthier Chantal
Unité de recherches sur les obésités, Institut National de la Santé et de la Recherche Médicale Unité 586, Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France.
Cardiovasc Res. 2003 Aug 1;59(2):288-96. doi: 10.1016/s0008-6363(03)00359-6.
The regulation of cardiac function by catecholamines involves three populations of beta-adrenoceptor (beta-AR). beta(1)- and beta(2)-AR stimulations produce an increase in contractility and beta(3)-AR stimulation mediates a negative inotropic effect in human ventricular muscle. Because of the lack of suitable animal models, we have generated transgenic mice with cardiac-specific expression of the human beta(3)-AR (TG beta(3) mice).
TG beta(3) mice were produced by microinjection of the human beta(3)-AR under the control of the alpha myosin heavy chain promoter. Phenotypic analyses comprised beta(3)-AR mRNA and protein determinations, histological studies, electrocardiogram, contractility and cyclic nucleotide measurements.
TG beta(3) mice presented no histological evidence of myocyte hypertrophy or fibrogenesis. In basal conditions, TG beta(3) mice were characterized by an increase in heart rate and an acceleration of twitch parameters without modification of its amplitude. beta(3)-AR agonists (CL 316243, SR 58611A) decreased contractility at low concentrations (1-100 nM). At high concentrations, the negative inotropic effect was abolished. Pretreatment with nadolol, a beta(1)/beta(2)-AR blocker, blunted the rebound in peak tension elicited by beta(3)-AR agonists suggesting a non-specific action of these compounds on beta(1)- and beta(2)-AR. The involvement of beta(3)-AR in the negative inotropic effect was confirmed by the pretreatment with bupranolol, a non-selective beta-AR antagonist, which fully abolished the effects of SR 58611A. The negative inotropic effect was associated with an increase in intracellular cGMP level.
We conclude that cardiac overexpression of beta(3)-AR in mice reproduces ex vivo the negative inotropic effects obtained with beta(3)-AR stimulation in human ventricular tissues.
儿茶酚胺对心脏功能的调节涉及三类β -肾上腺素能受体（β -AR）。β1 -和β2 -AR激动可增强心肌收缩力，而β3 -AR激动则介导人心室肌负性变力作用。由于缺乏合适的动物模型，我们构建了心脏特异性表达人β3 -AR的转基因小鼠（TGβ3小鼠）。
通过显微注射将α -肌球蛋白重链启动子调控下的人β3 -AR导入小鼠，构建TGβ3小鼠。表型分析包括β3 -AR mRNA和蛋白测定、组织学研究、心电图、收缩力及环核苷酸测量。
TGβ3小鼠未出现心肌细胞肥大或纤维化的组织学证据。在基础状态下，TGβ3小鼠表现为心率增加和抽搐参数加快，但其幅度未改变。β3 -AR激动剂（CL 316243、SR 58611A）在低浓度（1 - 100 nM）时可降低收缩力。在高浓度时，负性变力作用消失。用β1 /β2 -AR阻滞剂纳多洛尔预处理可减弱β3 -AR激动剂引起的峰值张力反弹，提示这些化合物对β1 -和β2 -AR有非特异性作用。用非选择性β -AR拮抗剂布普萘洛尔预处理可完全消除SR 58611A的作用，证实了β3 -AR参与负性变力作用。负性变力作用与细胞内cGMP水平升高有关。
我们得出结论，小鼠心脏中β3 -AR的过表达在体外再现了人心室组织中β3 -AR激动所产生的负性变力作用。
