Du X J, Vincan E, Percy E, Woodcock E A
Baker Medical Research Institute, Melbourne, Australia.
J Auton Nerv Syst. 2000 Mar 15;79(2-3):108-16. doi: 10.1016/s0165-1838(00)00070-9.
Transgenic (TG) mice overexpressing beta(2)-adrenoceptors (AR) in the heart have enhanced beta-adrenergic activity. Since the degree of beta-adrenergic activation influences the negative chronotropic control of heart rate (HR), we studied the inhibitory effect of cholinergic and purinergic stimulation on HR in TG and wild-type (WT) control mice. Bradycardia in response to vagal nerve stimulation and administration of acetylcholine or adenosine was studied in anesthetised animals and perfused hearts. Basal HR was significantly higher in TG than WT mice (P<0.01). Electrical stimulation of vagal nerves (1-32 Hz) induced a Hz-dependent reduction in HR and the response was more pronounced in TG than WT groups (P<0.01). In perfused hearts, HR reduction by acetylcholine (ACh) was more pronounced with EC(50) 110-fold lower in TG than WT hearts. Adenosine-induced bradycardia, which was abolished by a P(1) antagonist, was more pronounced in TG hearts. After pre-treatment with pertussis toxin (PT, 100 microg/kg), bradycardia by vagal nerve stimulation or ACh remained unchanged in WT, but markedly inhibited in TG hearts (both P<0.01). Conversely, inhibiting guanylyl cyclase with LY83583 (30 microM) or nitric oxide synthase with L-NMMA (100 microM) attenuated HR reduction by vagal nerve stimulation in WT but not in TG hearts. Immunobloting assay showed similar G(ialpha2) abundance in TG and WT hearts. Thus, cardiac overexpression of beta(2)AR with high beta-adrenergic activity leads to hypersensitivity of inhibitory receptors controlling HR due to increase in activity of PT-sensitive G-proteins.
心脏中过表达β₂ - 肾上腺素能受体（AR）的转基因（TG）小鼠具有增强的β - 肾上腺素能活性。由于β - 肾上腺素能激活程度会影响心率（HR）的负性变时控制，我们研究了胆碱能和嘌呤能刺激对TG小鼠和野生型（WT）对照小鼠心率的抑制作用。在麻醉动物和灌注心脏中研究了迷走神经刺激以及乙酰胆碱或腺苷给药引起的心动过缓。TG小鼠的基础心率显著高于WT小鼠（P<0.01）。迷走神经电刺激（1 - 32 Hz）引起心率呈频率依赖性降低，且TG组的反应比WT组更明显（P<0.01）。在灌注心脏中，乙酰胆碱（ACh）引起的心率降低在TG心脏中更明显，其半数有效浓度（EC₅₀）比WT心脏低110倍。腺苷诱导的心动过缓（可被P₁拮抗剂消除）在TG心脏中更明显。用百日咳毒素（PT，100μg/kg）预处理后，WT小鼠中迷走神经刺激或ACh引起的心动过缓保持不变，但在TG心脏中显著受到抑制（均为P<0.01）。相反，用LY83583（30μM）抑制鸟苷酸环化酶或用L - NMMA（100μM）抑制一氧化氮合酶可减弱WT心脏中迷走神经刺激引起的心率降低，但对TG心脏无此作用。免疫印迹分析显示TG和WT心脏中G（iα₂）丰度相似。因此，具有高β - 肾上腺素能活性的β₂AR在心脏中的过表达由于PT敏感型G蛋白活性增加，导致控制心率的抑制性受体超敏。
