Abnormal Myocardial Contraction in α1A- and α1B-adrenoceptor double-knockout mice
Abnormal Myocardial Contraction in α1A- and α1B-adrenoceptor double-knockout mice
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DOI：
10.1016/s0022-2828(03)00227-x
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发表时间：
2003-10-01
影响因子：
5
通讯作者：
Baker, AJ
中科院分区：
文献类型：
--
作者：
McCloskey, DT;Turnbull, L;Baker, AJ
我们使用双基因敲除小鼠（ABKO）缺乏两种主要的心肌α（1）-肾上腺素能受体（AR）亚型（α（1A）和α（1B）），以确定是否α（1）-AR是正常心肌收缩所必需的。Langendorff灌注的ABKO心脏具有比野生型（WT）心脏更高的发育压力（123 +/-3mmHg，n = 22对103 +/-3mmHg，n = 38，P <0.001）。用哌唑嗪急性抑制WT心脏中的α（1）-AR不会增加压力，这表明ABKO心脏的压力增加是由收缩的长期营养效应介导的，而不是α（1）-AR去除的直接调节效应。与灌注心脏相似，ABKO心室小梁在2 mM细胞外[Ca2 +]下的次最大力高于WT（11.4 ± 1.7 vs.6.9 ± 0.6 mN/mm（2），n = 8，P <0.05）;然而，Fura-2 Ca2+瞬变峰没有差异（0.79 +/-0.11 vs.0.75 +/-0.16 μ M，n = 10 - 12，P> 0.05），表明ABKO心肌具有增加的肌丝Ca2+敏感性。使用强直法测量Ca 2 +-力关系支持了这一结论。肌丝Ca2+敏感性的增加不能用细胞内pH解释，ABKO和WT之间没有差异（7.41 +/-0.01对7.39 +/-0.02，n = 4 - 6，P> 0.05;来自BCECF荧光）。然而，ABKO显示肌钙蛋白I磷酸化受损，这可能发挥了作用。与增加的次最大力相反，在高细胞外[Ca2 +]下，ABKO小梁的最大力低于WT（29.6 +/-1.9 vs. 37.6 +/-1.4 mN/mm（2），n = 7，P <0.01）。然而，胞浆[Ca 2 +]峰值无差异（1.13 +/-0.15 vs. 1.19 +/-0.04 μ M，n = 6 - 7，P> 0.05），表明ABKO心肌肌丝功能受损。最后，ABKO心肌对β-AR刺激的反应性降低。我们得出结论：α（1）-AR是正常心肌收缩所必需的; α（1）-AR介导对收缩的长期营养作用; α（1）-AR功能的丧失导致在心力衰竭中也发现的一些功能异常。(C)2003 Elsevier Ltd.保留所有权利。
We used double-knockout mice (ABKO) lacking both predominant myocardial alpha(1)-adrenergic receptor (AR) subtypes (alpha(1A) and alpha(1B)) to determine if alpha(1)-ARs are required for normal myocardial contraction. Langendorff-perfused ABKO hearts had higher developed pressure than wild type (WT) hearts (123 +/- 3 mmHg n = 22 vs. 103 +/- 3 mmHg, n = 38, P < 0.001). Acutely inhibiting alpha(1)-ARs in WT hearts with prazosin did not increase pressure, suggesting that the increased pressure of ABKO hearts was mediated by long-term trophic effects on contraction rather than direct regulatory effects of alpha(1)-AR removal. Similar to perfused hearts, ABKO ventricular trabeculae had higher submaximal force at 2 mM extracellular [Ca2+]than WT (11.4 +/- 1.7 vs. 6.9 +/- 0.6 mN/mm(2), n = 8, P < 0.05); however, the peaks of fura-2 Ca2+ transients were not different (0.79 +/- 0.11 vs. 0.75 +/- 0.16 muM, n = 10-12, P > 0.05), suggesting ABKO myocardium had increased myofilament Ca2+-sensitivity. This conclusion was supported by measuring the Ca2+-force relationship using tetanization. Increased myofilament Ca2+-sensitivity was not explained by intracellular pH, which did not differ between ABKO and WT (7.41 +/- 0.01 vs. 7.39 +/- 0.02, n = 4-6, P > 0.05; from BCECF fluorescence). However, ABKO displayed impaired troponin I phosphorylation, which may have played a role. In contrast to increased submaximal force, ABKO trabeculae had lower maximal force than WT at high extracellular [Ca2+] (29.6 +/- 1.9 vs. 37.6 +/- 1.4 mN/mm(2), n = 7, P < 0.01). However, peak cytosolic [Ca2+] was not different (1.13 +/- 0.15 vs. 1.19 +/- 0.04 muM, n = 6-7, P > 0.05), suggesting ABKO myocardium had impaired myofilament function. Finally, ABKO myocardium had decreased responsiveness to beta-AR stimulation. We conclude: alpha(1)-ARs are required for normal myocardial contraction; alpha(1)-ARs mediate long-term trophic effects on contraction; loss of alpha(1)-AR function causes some of the functional abnormalities that are also found in heart failure. (C) 2003 Elsevier Ltd. All rights reserved.