Cubeddu L X, Weiner N
J Pharmacol Exp Ther. 1975 Jun;193(3):757-75.
A reserpine-like agent, 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7,-hexa-hydro-11b-H-benzo[a]quinolizine (BQZ), at concentrations that do not inhibit phosphodiesterase activity, produces a marked increase in the outflow of 3-H-dihydroxyphenyl-ethyleneglycol from the isolated, perfused cat slpeen prelabeled with 3-H-norepinephrine (3-H-NE). The increased intraneuronal levels of catechols probably account for the inhibition of the conversion of 1-minus14C-L-tyrosine to 1-minus14C-L-dopa which is observed in the presence of the drug. In addition, in the presence of 0.9 muM BQZ, there is a 2.5- to 3-fold increase in the nerve stimulation-mediated overflow of NE, 3-H-NE, total 3-H and dopamine-beta-hydroxylase activity. A highly significant positive correlation was observed between the increase in the spontaneous release of 3-H and the enhanced exocytotic release of transmitter by nerve stimulation. These results suggest that either a primary alteration of the storage granule membrane or the subsequent enhanced intraneuronal levels of NE or NE metabolites may be responsible for the enhanced exocytotic release by nerve stimulation. In the presence of 0.9 muM BQZ, addition of 3 muM cocaine produces an increase in the nerve stimulation-mediated overflow of NE and an inhibition of the formation of 3-H-dihydroxyphenylethyleneglycol. In addition, there is a 20 to 30% decrease in the overflow of 3-H and dopamine-beta-hydroxylase activity and a marked delay in the outflow of the enzyme elicited by nerve stimulation. These results suggested that, in the presence of BQZ, a large fraction of the NE released during nerve stimulation is recaptured into the nerve terminals where it is subsequently metabolized to 3-H-dihydroxyphenylethyleneglycol. The enhanced exocytotic release of NE, the extensive presynaptic metabolism of the recaptured transmitter subsequent to release by nerve stimulation, and inhibition of norepinephrine synthesis all appear to contribute to the accelerated depletion of tissue NE which is observed when the splenic nerves are stimulated in the presence of 0.9 muM BQZ. These results provide an explanation for the accelerated depletion of tissue NE in animals treated with reserpine-like compounds when the sympathetic innervation is intact.
一种类似利血平的药物，2-羟基-2-乙基-3-异丁基-9,10-二甲氧基-1,2,3,4,6,7-六氢-11b-H-苯并[a]喹嗪（BQZ），在不抑制磷酸二酯酶活性的浓度下，能使预先用3-H-去甲肾上腺素（3-H-NE）标记的离体灌注猫脾脏中3-H-二羟基苯乙二醇的流出量显著增加。儿茶酚在神经元内水平的升高可能是该药物存在时观察到的1-14C-L-酪氨酸向1-14C-L-多巴转化受到抑制的原因。此外，在0.9μM BQZ存在的情况下，神经刺激介导的去甲肾上腺素（NE）、3-H-NE、总3-H和多巴胺-β-羟化酶活性的溢出增加了2.5至3倍。在3-H的自发释放增加与神经刺激增强递质的胞吐释放之间观察到高度显著的正相关。这些结果表明，要么是储存颗粒膜的原发性改变，要么是随后神经元内NE或NE代谢产物水平的升高，可能是神经刺激增强胞吐释放的原因。在0.9μM BQZ存在的情况下，添加3μM可卡因会使神经刺激介导的NE溢出增加，并抑制3-H-二羟基苯乙二醇的形成。此外，3-H和多巴胺-β-羟化酶活性的溢出减少20%至30%，并且神经刺激引起的该酶流出明显延迟。这些结果表明，在BQZ存在的情况下，神经刺激期间释放的大部分NE被重新摄取到神经末梢，随后在那里代谢为3-H-二羟基苯乙二醇。NE胞吐释放的增强、神经刺激释放后重新摄取的递质广泛的突触前代谢以及去甲肾上腺素合成的抑制，似乎都导致了在0.9μM BQZ存在下刺激脾神经时观察到的组织NE加速耗竭。这些结果为当交感神经支配完整时用类似利血平的化合物治疗的动物中组织NE加速耗竭提供了解释。
