Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766
Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766
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DOI：
10.3389/fphar.2020.00409
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发表时间：
2020-04-07
影响因子：
5.6
通讯作者：
Hennenberg, Martin
中科院分区：
文献类型：
--
作者：
Li Bingsheng;Yu Qingfeng;Hennenberg, Martin
膀胱过度活动（OAB）引起的下尿路症状（LUTS）是由自发性逼尿肌收缩引起的。用毒蕈碱受体拮抗剂或β(3)-肾上腺素受体激动剂治疗旨在抑制逼尿肌收缩，但总体效果不理想。因此，需要提高对膀胱平滑肌收缩的理解和对其抑制的新化合物的鉴定来开发替代方案。GTPase Rac1在前列腺平滑肌收缩中的作用已有报道，但在人类逼尿肌中的作用尚不清楚。在这里，我们研究了Rac抑制剂NSC23766和EHT1864对人逼尿肌组织收缩的影响。NSC23766也可能拮抗毒菌碱受体。方法取女性和男性膀胱根治性切除术后的逼尿肌组织。在器官浴中研究了NSC23766 （100 μ M）和EHT1864 （100 μ M）对逼尿肌收缩的影响。结果电场刺激诱导逼尿肌组织频率依赖性收缩，而NSC23766和EHT1864可抑制该作用。苯酚诱导浓度依赖性收缩。NSC23766对苯酚的浓度响应曲线右移，EC50值升高，但E-max值不变。EHT1864减少了碳苯酚诱导的收缩，导致碳苯酚的E-max值降低。血栓素类似物U46619诱导浓度依赖性收缩，NSC23766保持不变，但EHT1864减少。结论snsc23766和EHT1864抑制女性和男性逼尿肌收缩。NSC23766，而不是EHT1864竞争性拮抗毒蕈碱受体。除了神经源性和胆碱能性收缩外，EHT1864还能抑制血栓素A(2)诱导的逼尿肌收缩。后者可能是有希望的，因为OAB自发性逼尿肌收缩的起源是非胆碱能的。在体内，这两种化合物都可以改善oab相关的LUTS。
IntroductionLower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or beta(3)-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues.MethodsFemale and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 mu M) and EHT1864 (100 mu M) on detrusor contractions were studied in an organ bath.ResultsElectric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged E-max values. EHT1864 reduced carbachol-induced contractions, resulting in reduced E-max values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864.ConclusionsNSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A(2)-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS.