Lee Wei-Chia, Yu Hong-Ren, Tain You-Lin, Wu Kay L H, Chuang Yao-Chi, Chan Julie Y H
Division of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Department of Paediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Biomedicines. 2022 Oct 26;10(11):2716. doi: 10.3390/biomedicines10112716.
Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.
琥珀酸及其受体——G蛋白偶联受体91（GPR91），在代谢综合征（MetS）及其相关膀胱功能障碍中具有病理意义，尤其是在降低膀胱环磷酸腺苷（cAMP）水平和促进炎症方面。我们使用果糖喂养大鼠（FFRs）这一MetS大鼠模型，研究长春西汀（一种磷酸二酯酶-1抑制剂）和塞来昔布（一种选择性环氧化酶-2抑制剂）对MetS相关膀胱过度活动的影响。在FFRs中观察到膀胱过度活动的表型，包括排尿频率增加和膀胱测压中收缩间隔缩短，同时肝脏和血清中琥珀酸水平升高，肝脏和膀胱中GPR91表达下调。长春西汀和塞来昔布治疗改善了组织纤维化，并减轻了肝脏和膀胱中炎症细胞因子如白细胞介素-1β（IL-1β）的过度表达。在膀胱器官浴研究中，长春西汀治疗可恢复逼尿肌条对氯化钾、卡巴胆碱和福斯高林刺激的收缩和舒张反应，而塞来昔布则无此作用。在分子水平上，长春西汀和塞来昔布治疗调节了GPR91的下游信使（即细胞外信号调节激酶1/2（ERK1/2）和应激活化蛋白激酶（JNK）），抑制了膀胱中核因子κB（NF-κB）和IL-1β的表达，并防止了FFRs中观察到的纤维化。向膀胱器官浴中外源性应用琥珀酸可显著降低福斯高林诱导的逼尿肌产生的cAMP，而在长春西汀存在的情况下，这种降低明显恢复。总之，这些结果表明长春西汀可能通过恢复琥珀酸调节的逼尿肌cAMP产生并在膀胱逼尿肌中发挥抗炎作用，来减轻MetS相关的膀胱过度活动。
