Biers Suzanne M, Reynard John M, Brading Alison F
Department of Pharmacology, Oxford University, Oxford, UK.
BJU Int. 2006 Dec;98(6):1310-4. doi: 10.1111/j.1464-410X.2006.06564.x. Epub 2006 Oct 9.
To examine the effects of a new selective beta3-adrenoceptor agonist, GW427353 on human detrusor function, as beta2- and beta3-adrenoceptors have been identified in the bladder, and can mediate detrusor relaxation, but beta3-adrenoceptors are less widely distributed and beta3-adrenoceptor agonists should have the therapeutic advantage of producing fewer treatment side-effects.
'Normal' human detrusor was retrieved from 12 patients (mean age 56 years) at cystectomy and from organ donors. Detrusor strips (4 x 1 x 1 mm) were mounted in superfused organ baths. Tone was induced with carbachol (5 x 10(-7)m) before applying either a nonselective beta-adrenoceptor agonist (isoprenaline) or GW427353 (with or without the beta3-adrenoceptor antagonist, SR59230A). In addition, the effect of GW427353 was tested on intrinsic nerve-evoked smooth muscle contraction over time. Effects on spontaneous activity were also recorded.
GW427353 produced significant relaxation at concentrations of >10(-7)m; isoprenaline produced a significant effect from 10(-6)m, but otherwise both agonists had similar effects. The addition of SR59230A (10(-7)m), produced partial inhibition of the GW427353 response. GW427353 at 10(-6)m significantly reduced spontaneous activity within 10 min of incubation, and at higher concentrations (>5 x 10(-6)m) inhibited detrusor contractions evoked by electrical field stimulation.
Neuropathic bladder dysfunction is characterized by increased spontaneous activity and involuntary detrusor contractions, which can result in urinary frequency, urgency, nocturia and incontinence. The novel feature of GW427353 is the ability to suppress spontaneous activity and produce significant relaxation in human detrusor tissue at low concentrations, whilst also inhibiting evoked detrusor contractions at higher concentrations.
鉴于已在膀胱中鉴定出β2和β3肾上腺素能受体，且它们可介导逼尿肌舒张，但β3肾上腺素能受体分布较不广泛，β3肾上腺素能受体激动剂应具有产生较少治疗副作用的治疗优势，故研究新型选择性β3肾上腺素能受体激动剂GW427353对人逼尿肌功能的影响。
从12例患者（平均年龄56岁）膀胱切除术时及器官捐献者处获取“正常”人逼尿肌。将逼尿肌条（4×1×1毫米）安装在灌注式器官浴槽中。在应用非选择性β肾上腺素能受体激动剂（异丙肾上腺素）或GW427353（加或不加β3肾上腺素能受体拮抗剂SR59230A）之前，先用卡巴胆碱（5×10⁻⁷米）诱导张力。此外，测试了GW427353对内在神经诱发的平滑肌收缩随时间的影响。还记录了对自发活动的影响。
GW427353在浓度>10⁻⁷米时产生显著舒张；异丙肾上腺素从10⁻⁶米开始产生显著作用，但除此之外两种激动剂具有相似作用。加入SR59230A（10⁻⁷米）可部分抑制GW427353反应。10⁻⁶米的GW427353在孵育10分钟内显著降低自发活动，在更高浓度（>5×10⁻⁶米）时抑制电场刺激诱发的逼尿肌收缩。
神经源性膀胱功能障碍的特征是自发活动增加和逼尿肌不自主收缩，这可导致尿频、尿急、夜尿症和尿失禁。GW427353的新特点是能够在低浓度下抑制人逼尿肌组织的自发活动并产生显著舒张，同时在高浓度下抑制诱发的逼尿肌收缩。
