Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 431, 405 30 Gothenburg, Sweden.
Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 431, 405 30 Gothenburg, Sweden.
Auton Neurosci. 2020 Sep;227:102689. doi: 10.1016/j.autneu.2020.102689. Epub 2020 May 23.
Mechanical stretch of the urothelium induces the release of ATP that activates bladder afferent nerves. In the rat urinary bladder, ATP is also a contractile co-transmitter in the parasympathetic innervation. In isolated preparations, ATP evokes a urothelial release of acetylcholine that substantially contributes to ATP-evoked contractile responses. Currently we aimed to further examine the interactions of ATP and acetylcholine in the rat urinary bladder in two in vivo models. In the whole bladder preparation, atropine reduced ATP-evoked responses by about 50% in intact but denervated bladders, while atropine had no effect after denudation of the urothelium. In a split bladder preparation, reflex-evoked responses of the contralateral half were studied by applying stimuli (agonists or stretch) to the ipsilateral half. Topical administration of ATP and methacholine as well as of stretch induced contralateral reflex-evoked contractions. While topical administration of atropine ipsilaterally reduced the ATP- and stretch-induced contralateral contractions by 27 and 39%, respectively, the P2X purinoceptor antagonist PPADS reduced them by 74 and 84%. In contrary, the muscarinic M2-(M4)-selective receptor antagonist methoctramine increased the responses by 38% (ATP) and 75% (stretch). Pirenzepine (M1-selective antagonist) had no effect on the reflex. In vitro, in the absence of the reflex, methoctramine did not affect the ATP-induced responses. It is concluded that urothelial ATP potently induces the micturition reflex and stimulates urothelial release of acetylcholine. Acetylcholine subsequently acts on afferents and on the detrusor muscle. While muscarinic M2 and/or M4 receptors in the sensory innervation exert inhibitory modulation, muscarinic M3 receptors cause excitation.
机械拉伸尿路上皮会引起 ATP 的释放，从而激活膀胱传入神经。在大鼠膀胱中，ATP 也是副交感神经支配中的一种收缩共递质。在分离的制剂中，ATP 会引起尿路上皮释放乙酰胆碱，这对 ATP 引起的收缩反应有很大贡献。目前，我们旨在进一步研究在两种体内模型中 ATP 和乙酰胆碱在大鼠膀胱中的相互作用。在整个膀胱制剂中，在完整但去神经的膀胱中，阿托品使 ATP 引起的反应减少了约 50%，而在尿路上皮去角质后，阿托品没有影响。在分裂膀胱制剂中，通过对同侧半施加刺激（激动剂或拉伸）来研究对侧半的反射引起的反应。局部给予 ATP 和乙酰甲胆碱以及拉伸会引起对侧反射引起的收缩。虽然局部给予阿托品同侧减少了 ATP 和拉伸引起的对侧收缩分别为 27%和 39%，但 P2X 嘌呤能受体拮抗剂 PPADS 减少了 74%和 84%。相反，毒蕈碱 M2-（M4）-选择性受体拮抗剂甲硫胺增加了 38%（ATP）和 75%（拉伸）的反应。哌仑西平（M1-选择性拮抗剂）对反射没有影响。在体外，在没有反射的情况下，甲硫胺对 ATP 引起的反应没有影响。结论是，尿路上皮的 ATP 强烈诱导排尿反射，并刺激尿路上皮释放乙酰胆碱。乙酰胆碱随后作用于传入神经和逼尿肌。虽然感觉神经支配中的毒蕈碱 M2 和/或 M4 受体发挥抑制调节作用，但毒蕈碱 M3 受体引起兴奋。
