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首页> 外文期刊>International journal of immunopharmacology >Hydroxyzine inhibits neurogenic bladder mast cell activation.
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Hydroxyzine inhibits neurogenic bladder mast cell activation.

机译：羟嗪抑制神经源性膀胱肥大细胞活化。

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OBJECTIVES: Increased numbers of activated mast cells have been documented close to substance P (SP) containing nerve endings in the bladders of patients with interstitial cystitis (IC), a painful, sterile bladder disorder occurring primarily in females. Many of these patients also suffer from allergies, but common antihistamines do not help. In line with the fact that IC symptoms worsen under stress, we recently showed that bladder mast cells could be activated by the stable acetylcholine (Ach) analogue carbachol and by immobilization stress. Preliminary data from open label studies indicated that the heterocyclic histamine-1 receptor antagonist (H-1r alpha) hydroxyzine reduces IC symptoms. We, therefore, investigated whether hydroxyzine could inhibit carbachol-induced bladder mast cell activation. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with 10(-5) M carbachol, 10(-5) M SP, or 100 microg/ml compound 48/80 (C48/80), with or without preincubation with the designated concentrations of the H-1r alpha. Mast cell activation was assessed by release of exogenous 3H-serotonin and morphological evidence of secretion by light microscopy. RESULTS: Carbachol at 10(-5) M triggered rat bladder mast cell serotonin release which represented a 65% increase over control. Equimolar concentrations of SP caused a 32% increase, while C48/80 had no effect. The heterocyclic piperazine H-1r alpha hydroxyzine reduced carbachol-induced serotonin release by 25% at 10(-6) M and 34% at 10(-5) M, both of which were statistically significant (P < 0.05). On the contrary, the well known H-1r alpha diphenhydramine had no inhibitory effect, while the mixed H-1r alpha and 5-hydroxytryptamine-receptor antagonist (5-HTr alpha) azatadine actually caused an 11% increase. CONCLUSION: Hydroxyzine reduced carbachol-induced serotonin release from rat bladder in vitro through a mechanism which was unrelated to its H-1 receptor antagonistic properties. The ability of hydroxyzine to inhibit bladder mast cell activation by neurogenic stimuli along with its anticholinergic, anxiolytic and analgesic properties, may explain the clinical efficacy of this drug in reducing IC symptoms. Other, nonsedating, hydroxyzine analogues able to inhibit bladder mast cell activation may provide potentially new therapeutic approaches for IC.
机译：目的：已记录到间质性膀胱炎（IC）患者膀胱中含有神经末梢的P物质（SP）附近的活化肥大细胞数量增加，这是一种痛苦，无菌的膀胱疾病，主要发生于女性。这些患者中许多也患有过敏症，但常见的抗组胺药无济于事。与IC症状在压力下恶化的事实相一致，我们最近表明，稳定的乙酰胆碱（Ach）类似物卡巴胆碱和固定应激可以激活膀胱肥大细胞。开放标签研究的初步数据表明，杂环组胺-1受体拮抗剂（H-1r alpha）羟嗪可减轻IC症状。因此，我们研究了羟嗪是否可以抑制卡巴胆碱诱导的膀胱肥大细胞活化。方法：对雄性Sprague-Dawley大鼠的膀胱碎片灌注10（-5）M卡巴胆碱，10（-5）M SP或100 microg / ml化合物48/80（C48 / 80），并进行或不进行预孵育。 H-1rα的指定浓度。通过释放外源性3H-血清素和光学显微镜观察分泌的形态学证据来评估肥大细胞的活化。结果：10（-5）M的卡巴胆碱可触发大鼠膀胱肥大细胞5-羟色胺释放，较对照组增加了65％。等摩尔浓度的SP引起32％的增加，而C48 / 80没有影响。杂环哌嗪H-1rα羟嗪在10（-6）M时将卡巴胆碱诱导的血清素释放减少25％，在10（-5）M时减少34％，两者在统计学上均具有显着性（P <0.05）。相反，众所周知的H-1rα-苯海拉明没有抑制作用，而混合的H-1rα和5-羟色胺受体拮抗剂（5-HTrα）氮杂他汀实际上引起了11％的增加。结论：羟嗪通过一种与其H-1受体拮抗特性无关的机制减少了卡巴胆碱诱导的大鼠血清5-羟色胺的释放。羟嗪通过神经源性刺激抑制膀胱肥大细胞激活的能力及其抗胆碱能，抗焦虑和镇痛特性，可以解释这种药物在减轻IC症状方面的临床功效。其他能够抑制膀胱肥大细胞活化的非镇静剂羟嗪类似物可能为IC提供潜在的新治疗方法。

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