School of Physiology & Pharmacology, Medical Sciences Building (P.S., J.F.R.P., A.E.P.), and School of Clinical Sciences (M.J.D.), University of Bristol, Bristol, United Kingdom.
J Pharmacol Exp Ther. 2013 Nov;347(2):506-15. doi: 10.1124/jpet.113.207340. Epub 2013 Sep 5.
Dysfunctions of the lower urinary tract, such as overactive bladder syndrome and incontinence, are the product of storage failure. Spontaneous regional bladder wall movements [nonmicturition contractions (NMCs)] are proposed to generate afferent activity that signals volume status to the central nervous system. The sympathetic nervous system, via activation of β-adrenoceptors (β-ARs), causes bladder relaxation and promotes urine storage. We hypothesized that β-AR regulation of micturition is mediated by suppression of NMCs. We used an unanesthetized, decerebrate, artificially perfused rat preparation that allows simultaneous cystometry with external urethral sphincter and pelvic afferent nerve recordings. Systemic isoprenaline (10 nM to 1 µM) increased intervoid interval and bladder compliance accompanied by a decrease in NMC amplitude, voiding pressure, and voiding threshold. Isoprenaline also reduced arterial pressure and increased heart rate. The β3-AR agonist mirabegron (10-100 nM) increased intervoid interval and bladder compliance and reduced NMC amplitude, yet preserved active voiding function and had no effect on arterial pressure or heart rate. All of these effects of mirabegron were blocked by the selective β3-AR antagonist N-[[3-[(2S)-2-hydroxy-3-[[2-[4-[(phenylsulfonyl)amino] phenyl]ethyl]amino]propoxy]phenyl]methyl]-acetamide (L748,337), which alone shortened intervoid interval and decreased bladder compliance-suggesting the presence of a basal β3-AR-mediated sympathetic tone. Similar effects of mirabegron were seen in an acetic acid-sensitized bladder preparation and in preparations after loss of spinobulbar reflex bladder control. The β3-AR-mediated increase in intervoid interval correlated with increased bladder compliance but not with the decrease in NMC amplitude. These findings indicate that β3-adrenoceptors have a selective effect that improves urine storage by increasing compliance without affecting the active components of voiding.
下尿路功能障碍，如膀胱过度活动症和尿失禁，是储存功能障碍的产物。自发性区域性膀胱壁运动（非排尿收缩（NMCs））被认为会产生传入活动，将容量状态信号传递给中枢神经系统。交感神经系统通过激活β-肾上腺素能受体（β-ARs）引起膀胱松弛并促进尿液储存。我们假设β-AR 对排尿的调节是通过抑制 NMCs 来介导的。我们使用了一种未麻醉的去大脑、人工灌注的大鼠制备物，该制备物允许同时进行膀胱测压和外部尿道括约肌和骨盆传入神经记录。全身异丙肾上腺素（10 nM 至 1 μM）增加了膀胱排空间隔和顺应性，同时降低了 NMC 幅度、排尿压力和排尿阈值。异丙肾上腺素还降低了动脉血压并增加了心率。β3-AR 激动剂米拉贝隆（10-100 nM）增加了膀胱排空间隔和顺应性，降低了 NMC 幅度，但保留了主动排尿功能，对动脉血压或心率没有影响。米拉贝隆的所有这些作用都被选择性β3-AR 拮抗剂 N-[[3-[(2S)-2-羟基-3-[[2-[4-[(苯基磺酰基)氨基]苯基]乙基]氨基]丙氧基]苯基]甲基]-乙酰胺（L748,337）阻断，该拮抗剂单独使用会缩短膀胱排空间隔并降低膀胱顺应性，表明存在基础的β3-AR 介导的交感神经张力。米拉贝隆在乙酸敏感的膀胱制备物中和在失去脊髓反射膀胱控制的制备物中也有类似的作用。米拉贝隆介导的膀胱排空间隔增加与膀胱顺应性增加相关，但与 NMC 幅度降低无关。这些发现表明，β3-肾上腺素能受体具有选择性作用，通过增加顺应性而不影响排尿的主动成分来改善储尿功能。
