Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy.
Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy.
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DOI：
10.1152/ajpheart.00569.2005
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发表时间：
2006-03
期刊：
影响因子：
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通讯作者：
C. Liang;Weike Mao;C. Iwai;S. Fukuoka;S. Y. Stevens
中科院分区：
文献类型：
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作者：
C. Liang;Weike Mao;C. Iwai;S. Fukuoka;S. Y. Stevens
心脏交感神经递质储存在衰竭的心脏中减少。在这项研究中，我们提出研究心脏交感神经递质的减少是否与充血性心力衰竭（CHF）间质去甲肾上腺素（NE）和活性氧的增加有关，使用微透析技术和水杨酸来检测。哦的一代。采用心室快速起搏（340次/分）和不采用心室快速起搏（340次/分）的家兔随机接受地西帕明（10毫克/天）或安慰剂治疗8周。快速起搏导致左室扩张和收缩功能障碍。衰竭心肌组织NE和酪氨酸羟化酶蛋白含量及活性均降低。与假手术组（0.26 +/- 0.03 ng/ml）相比，CHF组心肌间质NE增加（0.89 +/- 0.11 ng/ml）。此外，心肌间质组织测定显示，CHF动物心脏氧化应激升高。OH自由基，组织氧化谷胱甘肽，氧化线粒体DNA。在假手术或CHF动物中，去西帕明治疗产生了显著的NE摄取抑制，其证据是静脉输注NE后，加压反应放大，心肌间质NE增加，但对心功能或血流动力学没有显著影响。然而，去西帕明治疗减轻了CHF组织NE和酪氨酸羟化酶蛋白的减少和活性。地西帕明还能阻止NE在PC12细胞中产生的酪氨酸羟化酶的减少。因此，心脏交感神经递质的减少与CHF间质NE和组织氧化应激的增加有关。此外，NE或其氧化代谢物发挥其神经毒性作用需要正常的神经元摄取NE。
Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.