Vayssettes-Courchay Christine, Bouysset Françoise, Cordi Alex, Laubie Michel, Verbeuren Tony J
Division of Angiology, Servier Research Institute, 11 rue des Moulineaux, 92150, Suresnes, France.
Eur J Pharmacol. 2002 Oct 25;453(2-3):287-97. doi: 10.1016/s0014-2999(02)02456-1.
The effect of alpha2-adrenoceptor blockade in the medulla was studied in pentobarbital anesthetized rats in which arterial blood pressure, heart rate and renal sympathetic nerve activity were analysed. Three series of experiments were performed: (1) i.c. administration of alpha2-adrenoceptor antagonists with different subtype affinities; (2) i.v. administration of methoxy-idazoxan to study its effects on neuronal activity into the rostral ventral medulla; (3) microinjections of methoxy-idazoxan in rostral ventral medulla and nucleus tractus solitarii. Methoxy-idazoxan (0.1-3 microg x kg(-1) i.c., n=5), but not saline, rauwolscine, BRL 44408 (2-[2H-(1,3,dihydroisoindol)methyl]-4,5dihydroimidazol) or ARC 239 (2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquilindione) (each at 10-100 microg x kg(-1) i.c., n=5-5-6-5, respectively), increased mean arterial blood pressure, heart rate and renal nerve activity (+19+/-6 mm Hg, +72+/-22 beats x min(-1), +43+/-9%) and blocked the sympatho-inhibitory action of clonidine (10 microg x kg(-1) i.v.). In further experiments, methoxy-idazoxan, BRL 44408 and the highest dose of rauwolscine i.c., reversed the clonidine-induced sympatho-inhibition (order of potency: methoxy-idazoxan>BRL4440>rauwolscine, n=6 each), whereas ARC 239 (n=5) or saline (n=7) did not. Methoxy-idazoxan i.v. (n=7, 10-100 microg x kg(-1)) increased the renal sympathetic nerve and rostral ventral medulla neuronal activity and the heart rate (+36+/-7%, +66+/-29% and +18+/-9 beats x min(-1)) without a significant effect on mean arterial blood pressure. Microinjection of methoxy-idazoxan (1 nmol/40 nl) into the rostral ventral medulla reversed the effect of clonidine microinjected into the same site (2 nmol/40 nl, n=5). In another group of rats (n=8), methoxy-idazoxan increased mean arterial blood pressure, heart rate and renal nerve activity (+16+/-2 mm Hg, +42+/-7 beats x min(-1), +24+/-5%) and blocked the effect of clonidine i.v. (10 microg x kg(-1)). Bilateral microinjections into the nucleus tractus solitarii (n=5) did not alter mean arterial blood pressure but decreased heart rate and sympathetic nerve activity (-30+/-16 beats x min(-1), -20+/-14%). Our results offer direct in vivo evidence for the main role of the alpha2A/D-adrenoceptors located in the ventral pressor area. The data show that the sympathy-excitatory effect of alpha2-adrenoceptor antagonists is due to the blockade of a tonic activation of these alpha2A/D-adrenoceptors present in the rostral ventral pressor area.
在戊巴比妥麻醉的大鼠中研究了延髓中α2-肾上腺素能受体阻断的作用，分析了动脉血压、心率和肾交感神经活动。进行了三组实验：（1）脑室内给予具有不同亚型亲和力的α2-肾上腺素能拮抗剂；（2）静脉注射甲氧基-咪唑克生以研究其对延髓头端腹外侧区神经元活动的影响；（3）在延髓头端腹外侧区和孤束核微量注射甲氧基-咪唑克生。甲氧基-咪唑克生（0.1 - 3μg·kg⁻¹，脑室内给药，n = 5），而非生理盐水、萝芙木碱、BRL 44408（2-[2H-(1,3-二氢异吲哚)甲基]-4,5-二氢咪唑）或ARC 239（2-[2-(4-(2-甲氧基苯基)哌嗪-1-基)乙基]-4,4-二甲基-1,3-(2H,4H)-异喹啉二酮）（各自10 - 100μg·kg⁻¹，脑室内给药，n分别为5 - 5 - 6 - 5），可增加平均动脉血压、心率和肾神经活动（分别增加19±6 mmHg、72±22次/分钟、43±9%），并阻断可乐定（10μg·kg⁻¹，静脉注射）的交感抑制作用。在进一步实验中，甲氧基-咪唑克生、BRL 44408和最高剂量的萝芙木碱脑室内给药可逆转可乐定诱导的交感抑制（效价顺序：甲氧基-咪唑克生 > BRL4440 > 萝芙木碱，每组n = 6），而ARC 239（n = 5）或生理盐水（n = 7）则不能。静脉注射甲氧基-咪唑克生（n = 7，10 - 100μg·kg⁻¹）可增加肾交感神经和延髓头端腹外侧区神经元活动以及心率（分别增加36±7%、66±29%和18±9次/分钟），而对平均动脉血压无显著影响。向延髓头端腹外侧区微量注射甲氧基-咪唑克生（1 nmol/40 nl）可逆转向同一部位微量注射可乐定（2 nmol/40 nl，n = 5）的作用。在另一组大鼠（n = 8）中，甲氧基-咪唑克生增加平均动脉血压、心率和肾神经活动（分别增加16±2 mmHg、42±7次/分钟、24±5%），并阻断静脉注射可乐定（10μg·kg⁻¹）的作用。向孤束核双侧微量注射（n = 5）未改变平均动脉血压，但降低了心率和交感神经活动（降低30±16次/分钟、20±14%）。我们的结果为位于腹侧升压区的α2A/D-肾上腺素能受体的主要作用提供了直接的体内证据。数据表明，α2-肾上腺素能拮抗剂的交感兴奋作用是由于阻断了延髓头端腹侧升压区中这些α2A/D-肾上腺素能受体的紧张性激活。
