Gao Lie, Wang Wei, Li Yu-Long, Schultz Harold D, Liu Dongmei, Cornish Kurtis G, Zucker Irving H
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Circ Res. 2004 Oct 29;95(9):937-44. doi: 10.1161/01.RES.0000146676.04359.64. Epub 2004 Sep 30.
Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase-derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5+/-13.3% of control) and CHF (193.6+/-11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (P<0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPH-dependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT1) receptor and subunits of NAD(P)H oxidase (p40phox, p47phox, and gp91phox) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF.
慢性心力衰竭（CHF）常与交感神经系统兴奋相关。这一事件被认为是CHF患者生存的负面预测指标。交感神经兴奋与中枢血管紧张素II（Ang II）之间存在因果联系。最近的研究表明，NAD(P)H氧化酶衍生的活性氧（ROS）是Ang II信号传导的重要介质。在本研究中，我们检验了以下假设：在CHF状态下，中枢Ang II通过刺激NAD(P)H氧化酶和ROS来激活交感神经输出。通过慢性室性心动过速诱导雄性新西兰白兔发生CHF。利用动脉压无线电遥测和脑室内灌注技术，在清醒状态下进行实验。记录肾交感神经活动（RSNA）作为交感神经输出的直接指标。脑室内注射Ang II可使假手术组（为对照组的131.5±13.3%）和CHF组（为对照组的193.6±11.9%）兔子的RSNA显著增加。CHF组兔子的增加幅度显著大于假手术组兔子（P<0.01）。这些反应可被脑室内注射氯沙坦、tempol或阿朴吗啡消除。脑室内注射氯沙坦、tempol或阿朴吗啡可使CHF组兔子的静息RSNA显著降低，但对假手术组兔子无此作用。与CHF组兔子相比，脑室内注射超氧化物歧化酶抑制剂二乙基二硫代氨基甲酸盐可使假手术组兔子的RSNA显著增加更多。与假手术组兔子相比，CHF组兔子延髓头端腹外侧区（RVLM）中依赖NADPH的超氧阴离子生成增加了2.9倍。最后，在CHF组兔子中，RVLM中血管紧张素II 1型（AT1）受体以及NAD(P)H氧化酶亚基（p40phox、p47phox和gp91phox）的mRNA和蛋白表达增加。这些数据表明实验性CHF时脑自主神经区域存在强烈的自由基应激，并为Ang II和ROS作为CHF交感神经兴奋的促成因素之间的紧密关系提供了证据。
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