Yue J L, Okamura H, Goshima Y, Nakamura S, Geffard M, Misu Y
Department of Pharmacology, Yokohama City University School of Medicine, Japan.
Neuroscience. 1994 Sep;62(1):145-61. doi: 10.1016/0306-4522(94)90321-2.
We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system [Misu Y. and Goshima Y. (1993) Trends pharmac. Sci. 14, 119-123]. This study aimed to explore whether or not endogenous L-DOPA, as a neurotransmitter candidate of the primary baroreceptor afferents, tonically functions to activate depressor neurons in the nucleus tractus solitarii of anesthetized rats. By parallel microdialysis in bilateral nucleus tractus solitarii areas, the basal L-DOPA release was in part inhibited by tetrodotoxin perfusion (1 microM) or Ca2+ deprivation, and was markedly reduced by alpha-methyl-p-tyrosine (200 mg/kg, i.p.), a tyrosine hydroxylase inhibitor. Forty to 100 mM K+ concentration-dependently released L-DOPA. Fifty millimoles K+ repetitively and constantly released L-DOPA. This release was Ca(2+)-dependent. Stimulation of the left aortic nerve (100 Hz, 8 V) repetitively and constantly released L-DOPA and this release was tetrodotoxin-sensitive. Phenylephrine i.v. infused produced L-DOPA release and reflex bradycardia, temporally associated with a rise and subsequent recovery of blood pressure. This release and bradycardia were abolished by denervation of the bilateral carotid sinus and aortic nerves. In addition, L-DOPA methyl ester, a competitive L-DOPA antagonist, when microinjected into depressor sites of the left nucleus tractus solitarii, antagonized depressor responses to mild stimulation (20 Hz, 3 V) of the ipsilateral aortic nerve. This antagonist alone, microinjected bilaterally, elicited a dose-dependent hypertension, which was abolished by alpha-methyl-p-tyrosine. Furthermore, by immunocytochemical analysis seven days after denervation of the left aortic nerve, tyrosine hydroxylase- and L-DOPA-, but not dopamine- and dopamine-beta-hydroxylase-immunoreactivities decreased in the ipsilateral nucleus tractus solitarii and dorsal motor vagus nucleus complex area. In the left ganglion nodosum, denervation decreased staining and number of L-DOPA-immunoreactive cells and staining of tyrosine hydroxylase-immunoreactive cells, but no modification of dopamine-immunoreactive cells was seen. Taken together with previous findings that L-DOPA itself is stereoselectively responsible for cardiovascular control in this nucleus, it is probable that L-DOPA is a neurotransmitter of the primary baroreceptor afferents terminating directly in depressor neurons and/or indirectly in some neurons within a microcircuit, including depressor neurons of the nucleus tractus solitarii. Endogenously released L-DOPA itself tonically functions to activate depressor neurons for regulation of blood pressure in the rat nucleus tractus solitarii.
我们曾提出L-3,4-二羟基苯丙氨酸（L-DOPA）是中枢神经系统中的一种神经递质和/或神经调质[Misu Y.和Goshima Y.（1993年）《药理学趋势》14卷，119 - 123页]。本研究旨在探究内源性L-DOPA作为初级压力感受器传入神经的神经递质候选物，是否持续发挥作用以激活麻醉大鼠孤束核中的降压神经元。通过在双侧孤束核区域进行平行微透析，基础L-DOPA释放部分受到河豚毒素灌注（1微摩尔）或钙剥夺的抑制，并被酪氨酸羟化酶抑制剂α-甲基-对-酪氨酸（200毫克/千克，腹腔注射）显著降低。40至100毫摩尔钾离子浓度依赖性地释放L-DOPA。50毫摩尔钾离子反复且持续地释放L-DOPA。这种释放是钙依赖性的。刺激左主动脉神经（100赫兹，8伏）反复且持续地释放L-DOPA，且这种释放对河豚毒素敏感。静脉注射去氧肾上腺素会产生L-DOPA释放和反射性心动过缓，在时间上与血压升高及随后的恢复相关。双侧颈动脉窦和主动脉神经去神经支配后，这种释放和心动过缓消失。此外，L-DOPA甲酯是一种竞争性L-DOPA拮抗剂，当微量注射到左侧孤束核的降压部位时，可拮抗同侧主动脉神经轻度刺激（20赫兹，3伏）引起的降压反应。单独双侧微量注射这种拮抗剂会引发剂量依赖性高血压，α-甲基-对-酪氨酸可消除这种高血压。此外，通过免疫细胞化学分析，在左主动脉神经去神经支配7天后，同侧孤束核和迷走神经背核复合体区域中酪氨酸羟化酶和L-DOPA的免疫反应性降低，但多巴胺和多巴胺-β-羟化酶的免疫反应性未降低。在左侧结节神经节中，去神经支配减少了L-DOPA免疫反应性细胞的染色和数量以及酪氨酸羟化酶免疫反应性细胞的染色，但未观察到多巴胺免疫反应性细胞的改变。结合先前的研究结果，即L-DOPA本身在该核中对心血管控制具有立体选择性作用，L-DOPA很可能是直接终止于降压神经元和/或间接终止于微回路中某些神经元（包括孤束核降压神经元）的初级压力感受器传入神经的神经递质。内源性释放的L-DOPA本身持续发挥作用以激活降压神经元，从而调节大鼠孤束核中的血压。
