Luptak Jan, Kocmalova Michaela, Franova Sona, Sutovsky Juraj, Grendar Marian, Svihra Jan, Kliment Jan, Dusenka Robert, Sutovska Martina
Urology Clinic, Jessenius Faculty of Medicine, Martin University Hospital, Comenius University, Martin, Slovakia.
Gen Physiol Biophys. 2018 Jul;37(4):391-398. doi: 10.4149/gpb_2017064. Epub 2018 Jun 29.
This study specified the role of several key calcium-operating ion channels in contraction/relaxation of human detrusor muscle as possible target for overactive bladder (OAB) treatment. Detrusor samples, obtained from 18 males (average age 61.5 ± 5.9 years), were investigated by organ tissue bath method with following agents: diltiazem for L-type voltage-gated calcium channels; 3-fluropyridine-4-carboxylic acid (FPCA) for Orai-STIM channels; SKF 96365-hydrochloride for transient receptor potential (TRP) channels, T-type channels and Orai-STIM channels; 2- aminoethoxydiphenyl borate (2-APB) for inositol-triphosphate receptors (IP3Rs) and Orai-STIM channels. Oxybutynin and mirabegron were tested under the same conditions as controls. Mirabegron, 2-APB and FPCA exhibited the best suppressive effect on carbachol-induced detrusor contractility. As expressed by area under the contractile curve (AUCC), 2-APB, FPCA and mirabegron have similar AUCC: 1.79, 1.73, 1.73. The highest AUCC was 3.64 for diltiazem+SKF, followed by 3.21 for diltiazem, 3.16 for SKF and 2.94 for oxybutynin. The lowest median amplitude and contraction variability is for 2-APB followed by mirabegron and FPCA. There were significant differences between: 2-APB/FPCA vs.: ditiazem, diltiazem+SKF and SKF. Summary of results suggested the principal role of IP3Rs, Orai-STIM coupling and large-conductance calcium-activated potassium channels in detrusor contraction and pointed on Orai-STIM channels as possible targets for OAB pharmacotherapy.
本研究明确了几种关键的钙调控离子通道在人逼尿肌收缩/舒张中的作用，将其作为治疗膀胱过度活动症（OAB）的潜在靶点。从18名男性（平均年龄61.5±5.9岁）获取逼尿肌样本，采用器官组织浴法并用以下药物进行研究：地尔硫䓬用于L型电压门控钙通道；3-氟吡啶-4-羧酸（FPCA）用于Orai-STIM通道；盐酸SKF 96365用于瞬时受体电位（TRP）通道、T型通道和Orai-STIM通道；2-氨基乙氧基二苯硼酸（2-APB）用于肌醇三磷酸受体（IP3R）和Orai-STIM通道。奥昔布宁和米拉贝隆在相同条件下作为对照进行测试。米拉贝隆、2-APB和FPCA对卡巴胆碱诱导的逼尿肌收缩力表现出最佳抑制作用。以收缩曲线下面积（AUCC）表示，2-APB、FPCA和米拉贝隆的AUCC相似：分别为1.79、1.73、1.73。地尔硫䓬+SKF的AUCC最高，为3.64，其次是地尔硫䓬的3.21、SKF的3.16和奥昔布宁的2.94。2-APB的中位振幅和收缩变异性最低，其次是米拉贝隆和FPCA。2-APB/FPCA与地尔硫䓬、地尔硫䓬+SKF和SKF之间存在显著差异。结果总结表明，IP3R、Orai-STIM偶联和大电导钙激活钾通道在逼尿肌收缩中起主要作用，并指出Orai-STIM通道可能是OAB药物治疗的靶点。
