Carson Robert P, Diedrich André, Robertson David
Autonomic Dysfunction Center, Vanderbilt University, Nashville, Tennessee 37232-2195, USA.
J Appl Physiol (1985). 2002 Dec;93(6):2192-8. doi: 10.1152/japplphysiol.00033.2002. Epub 2002 Aug 23.
Orthostatic intolerance is a debilitating syndrome characterized by tachycardia on assumption of upright posture. The norepinephrine (NE) transporter (NET) has been implicated in a genetic form of the disorder. We assessed the combined central and peripheral effects of pharmacological NET blockade on cardiovascular regulation and baroreflex sensitivity in rats. NE reuptake was blocked chronically in female Sprague-Dawley rats by the NET antagonist desipramine (DMI). Treated animals demonstrated an elevated supine heart rate, reduced tyramine responsiveness, and a reduced plasma ratio of the intraneuronal NE metabolite dihydroxyphenylglycol relative to NE, all of which are consistent with observations in human NET deficiency. Spectral analysis revealed a dramatic decrease in low-frequency spectral power after DMI that was consistent with decreased sympathetic outflow. Stimulation of the baroreflex with the vasodilator nitroprusside revealed an attenuated tachycardia in DMI-treated animals. This indicated that the DMI-induced sympathoinhibitory effects of increased NE in the brain stem predominates over the functional elevation of NE stimulation of peripheral targets. Thus attenuated baroreflex function and reduced sympathetic outflow may contribute to the orthostatic intolerance of severe NET deficiency.
直立不耐受是一种使人衰弱的综合征，其特征为在采取直立姿势时出现心动过速。去甲肾上腺素（NE）转运体（NET）与该疾病的一种遗传形式有关。我们评估了药理学上的NET阻断对大鼠心血管调节和压力反射敏感性的中枢和外周联合作用。通过NET拮抗剂地昔帕明（DMI）对雌性Sprague-Dawley大鼠的NE再摄取进行长期阻断。接受治疗的动物表现出仰卧心率升高、对酪胺的反应性降低以及神经元内NE代谢物二羟苯乙二醇相对于NE的血浆比率降低，所有这些都与人类NET缺乏症中的观察结果一致。频谱分析显示，DMI处理后低频频谱功率显著降低，这与交感神经流出减少一致。用血管扩张剂硝普钠刺激压力反射显示，DMI处理的动物心动过速减弱。这表明，DMI诱导的脑干中NE增加的交感抑制作用超过了外周靶点NE刺激的功能增强。因此，压力反射功能减弱和交感神经流出减少可能导致严重NET缺乏的直立不耐受。
