Cohen M L, Schenck K W, Hemrick-Luecke S H
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA.
J Pharmacol Exp Ther. 1999 Sep;290(3):1195-201.
Although serotonergic receptor agonists are known to modulate release of central serotonin, less is known about the ability of serotonin to alter neurotransmission in peripheral adrenergic nerves. The present study used field stimulation (40V, 0.7 ms duration, 1-16 Hz) to contract the rabbit saphenous vein, an effect that was abolished in the presence of tetrodotoxin and prazosin (10(-6) M), consistent with stimulation of neuronal norepinephrine release. Furthermore, the field-stimulated contraction was not altered by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR127935 (10(-6) M), but was markedly inhibited by the 5-HT(1A) receptor antagonist WAY 100635 (10(-6) M). GR127935 (10(-8) M) inhibited contraction to sumatriptan, documenting that the concentration used was sufficient to block 5-HT(1B/1D-like) vascular receptors in this tissue. Likewise, WAY 100635 (10(-6) M) inhibited contraction to the 5-HT(1A) receptor agonists (+/-)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) and LY238729, without altering contraction to norepinephrine or sumatriptan. Furthermore, both 8-OH-DPAT and LY228729 enhanced the contractile response to field stimulation (1. 0-8.0 Hz) and activated norepinephrine release in the absence of field stimulation. Contractile responses of the rabbit saphenous vein to both 5-HT(1A) receptor agonists were markedly inhibited by prazosin and dextrally shifted by WAY 100635, supporting the idea that the 5-HT(1A) receptor agonists were activating presynaptic 5-HT(1A) receptors to enhance norepinephrine release even in the absence of field stimulation. Thus, in the rabbit saphenous vein, 5-HT(1A) but not 5-HT(1B/1D) receptors enhanced neurotransmitter release from adrenergic nerves. These observations suggested that serotonergic nerves or other cell types in the saphenous vein are activated by field stimulation to release serotonin, which in turn activates presynaptic 5-HT(1A) receptors on adrenergic neurons to effect norepinephrine release. To support this hypothesis, serotonin levels were measured in the saphenous vein and were increased after pargyline pretreatment (30 mg/kg s.c.), decreased after dl-p-chlorophenylalanine methyl ester pretreatment (300 mg/kg s.c.), and unaltered after pretreatment with 6-hydroxydopamine hydrobromide (100 mg/kg s.c.). Thus, we provide strong evidence for the 1) presence of serotonin and its direct synthesis independent of adrenergic nerves and 2) a novel excitatory effect of presynaptic 5-HT(1A) receptor activation on adrenergic nerves in a peripheral blood vessel.
尽管已知血清素能受体激动剂可调节中枢血清素的释放，但血清素改变外周肾上腺素能神经中神经传递的能力却鲜为人知。本研究采用场刺激（40V，持续时间0.7ms，1 - 16Hz）使兔隐静脉收缩，在存在河豚毒素和哌唑嗪（10⁻⁶M）的情况下该效应消失，这与神经元去甲肾上腺素释放的刺激一致。此外，5 - 羟色胺（5 - HT）（1B/1D）受体拮抗剂GR127935（10⁻⁶M）未改变场刺激引起的收缩，但5 - HT（1A）受体拮抗剂WAY 100635（10⁻⁶M）显著抑制了该收缩。GR127935（10⁻⁸M）抑制了对舒马曲坦的收缩反应，证明所用浓度足以阻断该组织中的5 - HT（1B/1D样）血管受体。同样，WAY 100635（10⁻⁶M）抑制了对5 - HT（1A）受体激动剂（±） - 8 - 羟基二丙基氨基四氢萘溴化物（8 - OH - DPAT）和LY238729的收缩反应，而不改变对去甲肾上腺素或舒马曲坦的收缩反应。此外，8 - OH - DPAT和LY228729均增强了对场刺激（1.0 - 8.0Hz）的收缩反应，并在无场刺激时激活了去甲肾上腺素的释放。兔隐静脉对两种5 - HT（1A）受体激动剂的收缩反应均被哌唑嗪显著抑制，并被WAY 100635向右移位，支持了5 - HT（1A）受体激动剂即使在无场刺激时也能激活突触前5 - HT（1A）受体以增强去甲肾上腺素释放的观点。因此，在兔隐静脉中，5 - HT（1A）而非5 - HT（1B/1D）受体增强了肾上腺素能神经的神经递质释放。这些观察结果表明，隐静脉中的血清素能神经或其他细胞类型被场刺激激活以释放血清素，进而激活肾上腺素能神经元上的突触前5 - HT（1A）受体以实现去甲肾上腺素释放。为支持这一假设，对隐静脉中的血清素水平进行了测量，在帕吉林预处理（30mg/kg皮下注射）后升高，在dl - 对氯苯丙氨酸甲酯预处理（300mg/kg皮下注射）后降低，在氢溴酸6 - 羟基多巴胺预处理（100mg/kg皮下注射）后未改变。因此，我们为以下两点提供了有力证据：1）血清素的存在及其独立于肾上腺素能神经的直接合成；2）突触前5 - HT（1A）受体激活对外周血管中肾上腺素能神经的一种新型兴奋作用。
