评估抗抑郁药对可乐定抑制的离体大鼠输精管电场刺激诱导收缩恢复的影响。

Obara Keisuke, Michino Mayumi, Ito Masataka, Ao Lin, Sawada Ayano, Yamaki Fumiko, Matsuo Kazuhiro, Yoshio Takashi, Tanaka Yoshio

Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.

Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Japan.

Pharmacology. 2019;103(3-4):189-201. doi: 10.1159/000495616. Epub 2019 Jan 29.

BACKGROUND

A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α2-adrenoceptor (α2-AR) is lacking.

OBJECTIVES

The present study was performed to evaluate the potential of clinically available antidepressants to reverse α2-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment.

METHOD

The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10-8 mol/L clonidine (a selective α2-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations.

RESULTS

The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT2A receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D2-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist).

CONCLUSIONS

These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α2-AR antagonism.

背景

目前尚无报告研究临床可用的抗抑郁药是否通过对α2肾上腺素能受体（α2-AR）的拮抗作用来增强尿道平滑肌收缩。

目的

进行本研究以评估临床可用抗抑郁药逆转大鼠输精管中α2-AR介导的收缩抑制的可能性，从而预测它们是否会导致排尿障碍。

方法

研究了18种不同类别的抗抑郁药对电场刺激（EFS）诱导的收缩的影响，该收缩在离体大鼠输精管中被10-8 mol/L可乐定（一种选择性α2-AR激动剂）抑制，并将其与各自的临床血药浓度相关联。

结果

可乐定抑制的EFS诱导的收缩在接近临床血药水平的浓度下，被阿米替林（一种三环类抗抑郁药）、米氮平（一种去甲肾上腺素能和特异性5-羟色胺能抗抑郁药）和曲唑酮（一种5-羟色胺5-HT2A受体拮抗剂）恢复。EFS诱导的收缩也被三甲丙咪嗪、氯米帕明（三环类抗抑郁药）、米安色林（一种四环类抗抑郁药）、舍曲林（一种选择性5-羟色胺再摄取抑制剂[SSRI]）和舒必利（一种多巴胺D2受体拮抗剂）恢复，尽管这些药物的浓度大大超过了其临床可达到的血药水平。EFS诱导的收缩未受到丙咪嗪、去甲替林、阿莫沙平（三环类抗抑郁药）、马普替林（一种四环类抗抑郁药）、氟伏沙明、帕罗西汀、艾司西酞普兰（SSRI）、米那普仑、度洛西汀（5-羟色胺和去甲肾上腺素再摄取抑制剂）和阿立哌唑（一种多巴胺部分激动剂）的显著影响。