慢性心衰状态下丘脑室旁核GABA_A和GABA_B受体介导的交感传出抑制作用发生钝化
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摘要
下丘脑室旁核与交感传出神经的紧张性调节作用有关。室旁核γ-氨基丁酸(GABA)能神经元调节功能的失衡可能导致心衰状态下交感神经系统活动增强。证实慢性心衰大鼠下丘脑室旁核(PVN)γ-氨基丁酸(GABA)A和GABAB受体介导的紧张性抑制作用,比较观察慢性心衰状态下室旁核内GABAA和GABAB受体在调节交感缩血管紧张度发挥的作用。确证以下假说,即心衰状态下,室旁核内GABAA受体与GABAB受体介导的对交感传出神经紧张性抑制性作用的减弱机制可能与中枢PVN内GABAA受体与GABAB受体mRNA表达量的下调有关。以冠状动脉结扎法诱导大鼠心衰模型。使用α-氯醛糖和乌拉坦麻醉大鼠,于正常和心衰大鼠室旁核分别微量注射GABA-A受体激动剂(蝇蕈醇)和阻断剂(比扣扣灵)或GABA-B受体激动剂(CGP35348)和阻断剂(巴氯芬),观察其对大鼠心率、血压、肾交感神经放电的影响。分子生物学手段(RT-PCR):检测假手术组、心衰组大鼠室旁核内GABAA受体与GABAB受体mRNA表达量表达水平。目的是确定心衰过程交感神经激动的增强是否与中枢PVN内GABAA受体α1亚基与GABAB受体1a和1b亚型mRNA表达量水平的下调有关。通过对大鼠假手术组和心衰组大鼠血流动力学指标的测定,结果发现心衰组大鼠心率(HR)与对照组相比无显著差异;心衰组的动脉收缩压(SBP)、动脉舒张压(DBP)、平均动脉压(MBP)、左室收缩压(LVSP)和左心室内压最大收缩舒张速率(±dp/dt)明显低于假手术组;而心衰组大鼠左室舒张末期压(LVEDP)却明显高于假手术组;通过对假手术组、心衰组大鼠心脏标本进行病理分析,发现心衰组大鼠心脏重量、心脏重量与体重的比值与对照组相比明显增加;而左心室心肌梗死面积(MIS)与对照组相比明显增加,心梗面积在34%-42%之间或大于30%;而心衰组左心室壁最小厚度却明显低于对照组;通过制备大鼠心肌组织病理学切片,发现心衰组大鼠左心室发生了透壁性损伤。以上结果提示心衰组大鼠的心脏收缩功能减退、心肌肥厚并伴有心肌坏死和透壁性损伤,故认为心衰模型构建成功。通过制备大鼠脑组织冰冻切片,检验药物干预实验中,各种药物的微量注射位点位于室旁核范围内。在正常和心衰大鼠室旁核内微量注射GABA-A受体阻断剂甲碘荷包牡丹碱(Bicuculline methiodide)都导致心率、血压的升高和肾交感神经放电的显著增强,但是,在心衰组增强幅度与正常对照组比显著减小。分别在正常和心衰大鼠室旁核微量注射GABA-A受体激动剂蝇蕈醇(Musimol)都导致心率、血压下降和肾交感神经放电的减弱,但是心衰组的减弱幅度与正常对照组比显著减小。在正常和心衰大鼠室旁核内微量注射GABA-B受体阻断剂(CGP35348)都导致心率、血压的升高和肾交感神经放电的显著增强,但是,在心衰组增强幅度与正常对照组比显著减小。分别在正常和心衰大鼠室旁核微量注射GABA-B受体激动剂巴氯芬(Balcofen)都导致心率、血压下降和肾交感神经放电的减弱,但是心衰组的减弱幅度与正常对照组比显著减小。RT-PCR结果显示心衰组大鼠室旁核内GABAA受体α1亚基与GABAB受体1a和1b亚型mRNA表达量与假手术组相比发生下调。GABAA和GABAB受体参与介导室旁核的紧张性抑制作用,心衰大鼠室旁核GABAA和GABAB受体参与介导的紧张性抑制作用明显低于正常大鼠。结果提示慢性心衰状态下丘脑室旁核GABAA和GABAB受体介导的交感传出抑制作用发生钝化,可能与慢性心衰状态下交感活性增强有关。
The paraventricular nucleus (PVN) of the hypothalamus is involved in tonic regulation of sympathetic outflow. Impaired GABAergic control of PVN neurons may contribute to the elevated sympathetic drive in heart failure. To determine the role ofγ-aminobutyric acid (GABA)A and GABAB receptor in mediating the tonic inhibitory influence on the paraventricular nucleus (PVN) in rats with heat failure.Heart failure animal model was induced by coronary artery ligation. Inα-chloralose- and urethane-anaesthetized rats, microinjection of bicuculline(a GABA antagonist ) and muscimol(a GABA agonist ) into PVN was performed,and arterial blood pressure (BP) , heart rate (HR) and renal sympathetic nerve discharge (RSND) were observed in both sham-operated control and heart failure (HF) rats.The PCR determined that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were in CHF and sham rats. Microinjection of bicuculline (0.01-0.15 nmol), a GABAA receptor antagonist, into the PVN increased RSNA and ABP in Sham and HF rats in a dose dependent manner. This response was significantly attenuated in HF rats. Furthermore, the decrease in RSNA and ABP induced by a GABAA receptor agonist, muscimol (0.05-1.5 nmol), in the PVN was significantly less in HF rats than in sham-operated controls. In contrast, microinjection of GABAB receptor antagonist CGP35348 (0.15-3.0 nmol) into the PVN produced a dose-dependent increase in RSND, BP, and HR in both shamoperated control and HF rats. CGP35348 attenuated the increase in RSND and BP in HF rats compared with control rats. Alternatively, microinjection of the GABAB receptor agonist baclofen (0.3-4.5 nmol) into the PVN produced a dose-dependent decrease in RSND, BP, and HR in both control and HF rats. Baclofen was also less effective in decreasing RSND, BP, and HR in HF rats than in control rats. The PCR data showed that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were significantly lower in CHF than in sham rats. GABAA receptor and GABAB receptor mediates the tonic inhibitory influence on PVN,the inhibitory tonic influence mediated by GABAA receptor and GABAB receptor is smaller in HF rats.The current data suggest that the tonic inhibition mediated by both GABAA and GABAB receptors in the PVN on sympathetic outflow is blunted in CHF, which may be an important mechanism responsible for sympathetic hyperactivity in CHF.
The paraventricular nucleus (PVN) of the hypothalamus is involved in tonic regulation of sympathetic outflow. Impaired GABAergic control of PVN neurons may contribute to the elevated sympathetic drive in heart failure. To determine the role ofγ-aminobutyric acid (GABA)A and GABAB receptor in mediating the tonic inhibitory influence on the paraventricular nucleus (PVN) in rats with heat failure.Heart failure animal model was induced by coronary artery ligation. Inα-chloralose- and urethane-anaesthetized rats, microinjection of bicuculline(a GABA antagonist ) and muscimol(a GABA agonist ) into PVN was performed,and arterial blood pressure (BP) , heart rate (HR) and renal sympathetic nerve discharge (RSND) were observed in both sham-operated control and heart failure (HF) rats.The PCR determined that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were in CHF and sham rats. Microinjection of bicuculline (0.01-0.15 nmol), a GABAA receptor antagonist, into the PVN increased RSNA and ABP in Sham and HF rats in a dose dependent manner. This response was significantly attenuated in HF rats. Furthermore, the decrease in RSNA and ABP induced by a GABAA receptor agonist, muscimol (0.05-1.5 nmol), in the PVN was significantly less in HF rats than in sham-operated controls. In contrast, microinjection of GABAB receptor antagonist CGP35348 (0.15-3.0 nmol) into the PVN produced a dose-dependent increase in RSND, BP, and HR in both shamoperated control and HF rats. CGP35348 attenuated the increase in RSND and BP in HF rats compared with control rats. Alternatively, microinjection of the GABAB receptor agonist baclofen (0.3-4.5 nmol) into the PVN produced a dose-dependent decrease in RSND, BP, and HR in both control and HF rats. Baclofen was also less effective in decreasing RSND, BP, and HR in HF rats than in control rats. The PCR data showed that the mRNA expression levels of the GABAA receptorα1 subunit and the GABAB receptor 1a and 1b subtypes in the PVN were significantly lower in CHF than in sham rats. GABAA receptor and GABAB receptor mediates the tonic inhibitory influence on PVN,the inhibitory tonic influence mediated by GABAA receptor and GABAB receptor is smaller in HF rats.The current data suggest that the tonic inhibition mediated by both GABAA and GABAB receptors in the PVN on sympathetic outflow is blunted in CHF, which may be an important mechanism responsible for sympathetic hyperactivity in CHF.
引文
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[2]黄峻. 现代循证心脏病学[M]. 江苏科学技术出版社,2003. 94-124.
[3]刘亚欣, 周宪梁.β-肾上腺素能受体阻滞剂治疗慢性心力衰竭的研究进展[J]. 中国分子心脏病学杂志,2004,4(4):243-248.
[4] 陈瑞玲 , 赵志刚 . 神经内分泌拮抗剂治疗心力衰竭的研究进展 [J]. 中国临床药理学杂志,2006,22(4):307-309.
[5]殷凤,霍阳,陈悦.β 受体阻滞剂治疗慢性心力衰竭的研究进展[J]. 人民军医,2005,48(2):113-115.
[6]龚兰生, 施仲伟, 于金德. 充血性心力衰竭[M]. 第 1 版. 上海:上海科学技术出版社,2002. 44.
[7] 王 利 芳 , 张 雪 娥 . 内 皮 素 、 肿 瘤 坏 死 因 子 与 心 力 衰 竭 的 研 究 进 展 [J]. 医 学 综述,2006,12(23):1419-1421.
[8] 张 天 泰 . 内 皮 素 系 统 在 慢 性 心 力 衰 竭 中 作 用 的 研 究 进 展 [J]. 国 外 医 学 · 药 学 分册,2002 ,29(4):213-217.
[9]Zucker IH, Schultz H D, Li Y F, et al. The Origin of Sympathetic Outflow in Heart Failure: the Roles of Angiotensin II and Nitric Oxide[J]. Prog Biophys Mol Biol, 2004,84(2):217-232.
[10]朱国庆,王玮. 中枢血管紧张素对心血管活动调节作用[J]. 生理科学进展,2003,34(4):343-346.
[11] 虞燕琴 , 梁华为 , 夏强 . 下丘脑室旁核的心血管调节功能研究进展 [J]. 生理科学进展,2000,31(3):273-276.
[12]Anderson JW, Smith PM, Ferguson AV. Subfornical Organ Neurons Projecting to Paraventricular Nucleus: Whole-Cell Properties[J]. Brain Res, 2001,921(1):78-85.
[13]Cui LN, Coderre E, Renaud LP. Glutamate and GABA Mediate Suprachiasmatic Nucleus Inputs to Spinal-Projecting Paraventricular Neurons[J]. Am J Physiol Regul Integr Comp Physiol, 2001,281(4): 1283-1289.
[14]Cato MJ, Toney G M. Angiotensin II Excites Paraventricular Nucleus Neurons That Innervate the Rostral Ventrolateral Medulla: an in Vitro Patch-Clamp Study in Brain Slices[J]. J Neurophysiol, 2005, 93(1):403-413.
[15]Li DP, Pan HL. Angiotensin II Attenuates Synaptic GABA Release and Excites Paraventricular-Rostral Ventrolateral Medulla Output Neurons[J]. J Pharmacol Exp Ther, 2005, 313(3):1035-1045.
[16]虞燕琴, 夏强. 下丘脑室旁核的心血管调节功能及与心血管疾病的关系[J]. 浙江大学学报(医学版),2001,30(3):139-143.
[17]王智明,李云庆. 大鼠神经系统内 γ-氨基丁酸 B 受体 1 亚型的定位分布[J]. 解剖学报,2000,31(增刊):64-68.
[18]何晓兵,严缘昌. γ-氨基丁酸 B 受体(GABABR)研究最新进展[J]. 细胞生物学杂志,2002,24(4):217-223.
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