Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya, 467-8601, Japan.
Pflugers Arch. 2023 Nov;475(11):1315-1327. doi: 10.1007/s00424-023-02849-1. Epub 2023 Aug 17.
In isolated segments of the rat proximal colon, the dopamine reuptake inhibitor GBR 12909 (GBR) causes a dilatation, while the D-like receptor antagonist SCH 23390 (SCH) induces a tonic constriction, suggesting that neurally released dopamine tonically stimulates enteric inhibitory efferent neurons. Here, the targets of the enteric dopaminergic neurons were investigated. Cannulated segments of rat proximal colon were bathed in physiological salt solution and luminally perfused with 0.9% saline, while all drugs were applied to the bath. Spatio-temporal maps of colonic motility were constructed from video recordings of peristaltic contractions, and the maximum diameter was measured as an index of colonic contractility. GBR (1 μM)-induced dilatations of colonic segments were prevented by SCH (5 μM), L-nitro arginine (L-NA; 100 μM), a nitric oxide synthase inhibitor, or tetrodotoxin (0.6 μM). In contrast, constrictions induced by a higher concentration of SCH (20 μM) were unaffected by either L-NA or tetrodotoxin. The vasoactive intestinal peptide (VIP) receptor antagonist VIP (3 μM) or P2Y receptor antagonist MRS 2500 (1 μM) had no effect on either the GBR-induced dilatation or the SCH-induced constriction. In colonic segments that had been pretreated with 6-hydroxydopamine (100 μM, 3 h) to deplete enteric dopamine, GBR failed to increase the colonic diameter, while SCH was still capable of constricting colonic segments. Enteric dopaminergic neurons appear to project to nitrergic neurons to dilate the proximal colon by activating neuronal D-like receptors. In addition, constitutively activated D-like receptors expressed in cells yet to be determined may provide a tonic inhibition on colonic constrictions.
在大鼠近端结肠的孤立节段中，多巴胺再摄取抑制剂 GBR 12909（GBR）引起扩张，而 D 样受体拮抗剂 SCH 23390（SCH）引起紧张性收缩，表明神经释放的多巴胺紧张地刺激肠抑制传出神经元。在这里，研究了肠多巴胺能神经元的靶标。用生理盐溶液灌流大鼠近端结肠的插管段，并向腔内腔内灌注 0.9%生理盐水，同时向浴槽中给药。从蠕动收缩的视频记录构建结肠运动的时空图谱，并测量最大直径作为结肠收缩性的指标。GBR（1μM）诱导的结肠节段扩张被 SCH（5μM）、一氧化氮合酶抑制剂 L-硝基精氨酸（L-NA；100μM）或河豚毒素（0.6μM）阻止。相比之下，较高浓度的 SCH（20μM）引起的收缩不受 L-NA 或河豚毒素的影响。血管活性肠肽（VIP）受体拮抗剂 VIP（3μM）或 P2Y 受体拮抗剂 MRS 2500（1μM）对 GBR 诱导的扩张或 SCH 诱导的收缩均无影响。在已用 6-羟多巴胺（100μM，3h）预处理以耗尽肠多巴胺的结肠段中，GBR 未能增加结肠直径，而 SCH 仍能够收缩结肠段。肠多巴胺能神经元似乎投射到氮能神经元，通过激活神经元 D 样受体来扩张近端结肠。此外，在尚未确定的细胞中表达的组成性激活的 D 样受体可能对结肠收缩提供紧张性抑制。
