Grubb M C, Stornetta R L, Pence R, Baertschi A J, Guyenet P G
Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland 97201, USA.
J Auton Nerv Syst. 1998 Jul 15;71(2-3):85-95. doi: 10.1016/s0165-1838(98)00065-4.
The goal of the present study was to examine the effect of clonidine withdrawal on the neural control of blood pressure. Rats were treated for 7-13 days with clonidine via osmotic minipumps (200 microg kg(-1) day(-1), s.c.). Controls received saline or were sham operated. Withdrawal was precipitated by the alpha2-adrenergic receptor (alpha2-AR) antagonist atipamezole. Most experiments were done under halothane anesthesia. Chronic treatment with clonidine did not change mean arterial pressure (MAP) or heart rate (HR) but raised femoral artery resistance and the activity of locus coeruleus neurons slightly. Atipamezole given to rats treated chronically with clonidine produced the following effects: no change in MAP, severe tachycardia, sustained increase in splanchnic sympathetic nerve discharge (SND; +75 +/- 13%), transient increase in lumbar SND (+23 +/- 7%), ON-OFF activity pattern in the locus coeruleus (LC). The ON phase of LC activity was synchronized with upswings of SND and with small changes in MAP. A second alpha2-AR antagonist, methoxyidazoxan, produced effects identical to those of atipamezole. Atipamezole given to control rats produced no effect on MAP, HR, SND or LC activity. Atipamezole reversed the hypotension, sympathoinhibition and bradycardia produced by acute administration of clonidine. In awake rats treated chronically with clonidine, atipamezole did not change MAP but produced arterial pressure lability and tachycardia. In conclusion, under anesthesia, selective alpha2-AR antagonists elicit a clonidine withdrawal syndrome that displays autonomic characteristics reminiscent of the spontaneous withdrawal syndrome found in awake rats. The most prominent features of this syndrome are tachycardia, sympathoactivation, lack of hypertension and an oscillating activity pattern of brainstem neurons leading to abrupt changes in SND and in MAP.
本研究的目的是检测可乐定撤药对血压神经控制的影响。通过渗透微型泵（200μg·kg⁻¹·天⁻¹，皮下注射）给大鼠使用可乐定治疗7 - 13天。对照组接受生理盐水或假手术。通过α₂肾上腺素能受体（α₂ - AR）拮抗剂阿替美唑引发撤药反应。大多数实验在氟烷麻醉下进行。长期使用可乐定治疗并未改变平均动脉压（MAP）或心率（HR），但略微提高了股动脉阻力和蓝斑神经元的活性。给长期使用可乐定治疗的大鼠注射阿替美唑产生了以下效应：MAP无变化，严重心动过速，内脏交感神经放电（SND）持续增加（+75±13%），腰段SND短暂增加（+23±7%），蓝斑（LC）出现开 - 关活动模式。LC活动的开启阶段与SND的上升以及MAP的微小变化同步。第二种α₂ - AR拮抗剂甲氧基咪唑啉产生的效应与阿替美唑相同。给对照大鼠注射阿替美唑对MAP、HR、SND或LC活性无影响。阿替美唑逆转了急性给予可乐定所产生的低血压、交感神经抑制和心动过缓。在长期使用可乐定治疗的清醒大鼠中，阿替美唑未改变MAP，但产生了动脉压波动和心动过速。总之，在麻醉状态下，选择性α₂ - AR拮抗剂引发可乐定撤药综合征，该综合征表现出自主神经特征，让人联想到在清醒大鼠中发现的自发撤药综合征。该综合征最突出的特征是心动过速、交感神经激活、无高血压以及脑干神经元的振荡活动模式导致SND和MAP突然变化。
