Blebbistain, a myosin II inhibitor, as a novel strategy to regulate detrusor contractility in a rat model of partial bladder outlet obstruction.
Blebbistain, a myosin II inhibitor, as a novel strategy to regulate detrusor contractility in a rat model of partial bladder outlet obstruction.
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DOI：
10.1371/journal.pone.0025958
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
DiSanto ME
中科院分区：
文献类型：
--
作者：
Zhang X;Seftel A;DiSanto ME
部分膀胱出口梗阻（PBOO）是一种常见的泌尿系统病理学，主要由良性前列腺增生引起，可共存于40-45%的膀胱过度活动症（OAB）患者中，并与逼尿肌过度活动症（DO）相关。诱导DO的PBOO导致膀胱肌球蛋白II型和亚型组成的改变。Blebbistatin（BLEB）是一种肌球蛋白II抑制剂，我们最近证明了有效松弛正常逼尿肌平滑肌（SM），报告表明不同SM肌球蛋白（SMM）亚型和/或SMM与非肌肌球蛋白（NMM）的BLEB疗效不同。我们假设BLEB抑制肌球蛋白II作为一种新的收缩蛋白靶向策略，以调节DO。采用腹腔注射诱导的雄性大鼠PBOO模型，进行器官浴收缩、竞争性和Real-Time-RT-PCR。结果表明，梗阻膀胱重量增加2.74倍，逼尿肌对各种刺激的收缩力降低约50%沿着。梗阻也改变了逼尿肌的自发活动，振幅显著增加，但频率降低。PBOO将膀胱从相位型切换为更具张力型SM。5'肌球蛋白重链（MHC）可变剪接亚型SM-A（与张力型SM相关）的表达增加了3倍，而3' MHC SM 1和必需轻链亚型MLC 17 b的相对表达也增加了。总SMMHC表达降低了25%，而NMM IIB（SMemb）的表达大大增加了4.5倍。BLEB被发现完全放松逼尿肌条从假手术和PBOO大鼠预收缩与氯化钾，卡巴胆碱或电场刺激，虽然敏感性略有下降（20%），仅在较低剂量的PBOO。因此，我们提供了第一个彻底的表征大鼠膀胱肌球蛋白对PBOO的反应，并证明完全BLEB诱导的PBOO膀胱SM松弛。此外，本研究提供了有价值的证据表明，BLEB可能是一种新型的潜在的治疗药物，用于调节OAB的肌源性和神经诱发的DO。
Partial bladder outlet obstruction (PBOO), a common urologic pathology mostly caused by benign prostatic hyperplasia, can coexist in 40–45% of patients with overactive bladder (OAB) and is associated with detrusor overactivity (DO). PBOO that induces DO results in alteration in bladder myosin II type and isoform composition. Blebbistatin (BLEB) is a myosin II inhibitor we recently demonstrated potently relaxed normal detrusor smooth muscle (SM) and reports suggest varied BLEB efficacy for different SM myosin (SMM) isoforms and/or SMM vs nonmuscle myosin (NMM). We hypothesize BLEB inhibition of myosin II as a novel contraction protein targeted strategy to regulate DO. Using a surgically-induced male rat PBOO model, organ bath contractility, competitive and Real-Time-RT-PCR were performed. It was found that obstructed-bladder weight significantly increased 2.74-fold while in vitro contractility of detrusor to various stimuli was impaired ∼50% along with decreased shortening velocity. Obstruction also altered detrusor spontaneous activities with significantly increased amplitude but depressed frequency. PBOO switched bladder from a phasic-type to a more tonic-type SM. Expression of 5’ myosin heavy chain (MHC) alternatively spliced isoform SM-A (associated with tonic-type SM) increased 3-fold while 3’ MHC SM1 and essential light chain isoform MLC17b also exhibited increased relative expression. Total SMMHC expression was decreased by 25% while the expression of NMM IIB (SMemb) was greatly increased by 4.5-fold. BLEB was found to completely relax detrusor strips from both sham-operated and PBOO rats pre-contracted with KCl, carbachol or electrical field stimulation although sensitivity was slightly decreased (20%) only at lower doses for PBOO. Thus we provide the first thorough characterization of the response of rat bladder myosin to PBOO and demonstrate complete BLEB-induced PBOO bladder SM relaxation. Furthermore, the present study provides valuable evidence that BLEB may be a novel type of potential therapeutic agent for regulation of myogenic and nerve-evoked DO in OAB.
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影响因子：
2
作者：
Braverman, AS;Ruggieri, MR
通讯作者：
Ruggieri, MR
影响因子：
5.5
作者：
DiSanto, ME;Stein, R;Chacko, S
通讯作者：
Chacko, S
DOI：
10.1152/ajpcell.2001.280.2.c254
发表时间：
2001-02-01
影响因子：
5.5
作者：
Hypolite, JA;DiSanto, ME;Chacko, S
通讯作者：
Chacko, S
影响因子：
6.6
作者：
ABRAMS, PH;FARRAR, DJ;FENELEY, RCL
通讯作者：
FENELEY, RCL
DOI：
10.1152/ajpcell.1995.269.5.c1126
发表时间：
1995-11-01
影响因子：
5.5
作者：
CAI, S;FERGUSON, DG;PAUL, RJ
通讯作者：
PAUL, RJ