Histamine receptors rapidly desensitize without altering nerve-evoked contractions in murine urinary bladder smooth muscle.
Histamine receptors rapidly desensitize without altering nerve-evoked contractions in murine urinary bladder smooth muscle.
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组胺受体迅速脱敏，而不改变小鼠膀胱平滑肌神经诱发的收缩。
DOI：
10.1152/ajprenal.00355.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Tykocki,NathanR
中科院分区：
文献类型：
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作者：
Jones,BMalique;Mingin,GeraldC;Tykocki,NathanR
组胺作为导致感觉神经过敏的炎症介质，与膀胱功能障碍有关。然而，组胺对平滑肌的直接影响尚未得到彻底研究。我们假设组胺直接收缩膀胱平滑肌（UBSM），与对神经的影响无关。单细胞定量RT-PCR确定UBSM细胞上仅表达组胺H1和H2受体。在分离的组织浴实验中，组胺 (200 µM) 引起高度可变且快速脱敏的收缩，这种收缩被 H1 受体拮抗剂非索非那定 (5 µM) 和 Gq/11 抑制剂 YM254890 (1 µM) 完全消除。毒蕈碱受体拮抗剂阿托品 (1 µM)、Na+通道阻滞剂河豚毒素 (1 µM) 和瞬时受体电位 1 型香草酸拮抗剂辣椒西平 (10 µM) 均不会改变对组胺的反应，表明不涉及神经激活。 UBSM 对组胺的脱敏并非由于受体内化，因为胆固醇消耗剂甲基-β-环糊精 (10 mM)、动力介导的内吞作用抑制剂 dynasore (100 µM) 和网格蛋白介导的内吞作用抑制剂 pitstop2 (15 µM) 均不会增强或延长组胺收缩。来自脱敏组织的缓冲液仍然使未接触组胺的组织收缩，表明组胺没有被代谢。长时间暴露于组胺对电场刺激引起的收缩也没有影响，这表明传出神经和 UBSM 兴奋性均未改变。总之，这些数据表明，组胺虽然能够暂时收缩 UBSM，但不会对 UBSM 兴奋性或对传出神经输入的反应产生持久影响。因此，组胺直接对 UBSM 收缩性产生的任何急性影响不太可能改变膀胱功能。新的和值得注意的组胺通常与炎症性膀胱病理相关。我们试图研究组胺对膀胱收缩力的作用。组胺会收缩膀胱，但这种反应变化很大，并且会在几分钟内完全脱敏。这种脱敏不是由于受体的内化或组胺的代谢所致。由于组胺存在时神经诱发的收缩也不会增加，因此我们的研究结果表明组胺不会直接改变收缩性。
Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H1and H2receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 µM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H1receptor antagonist fexofenadine (5 µM) and the Gq/11inhibitor YM254890 (1 µM). Neither the muscarinic receptor antagonist atropine (1 µM), the Na+channel blocker tetrodotoxin (1 µM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 µM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-β-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 µM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 µM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function.NEW & NOTEWORTHYHistamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility.