Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction.
Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction.
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发表时间：
2002
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通讯作者：
C. Hampel;P. C. Dolber;Michael P. Smith;S. Savic;Joachim W Th roff;K. Thor;D. Schwinn
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作者：
C. Hampel;P. C. Dolber;Michael P. Smith;S. Savic;Joachim W Th roff;K. Thor;D. Schwinn
目的α 1肾上腺素能受体（α 1AR）拮抗剂可有效缓解膀胱出口梗阻患者的梗阻性和刺激性症状。虽然α 1aAR负责前列腺平滑肌松弛和出口梗阻缓解，但据我们所知，缓解刺激性症状的机制仍有待确定。因此，我们研究了膀胱α 1 AR亚型可能参与这一过程的机制。材料与方法：42只大鼠，包括6只未手术对照组，17只假手术对照组和19只梗阻组。对动物进行基线排尿模式表征，然后进行手术干预或假手术以建立梗阻（1.09 mm.开口受限）。6周后，为了使逼尿肌肥大发展，重新检查排尿行为，处死动物并立即将膀胱组织置于液氮中。使用定量竞争性逆转录酶-聚合酶链反应定量α 1 AR亚型信使（m）RNA，并使用与α 1 AR拮抗剂[125碘] 2-（-[4-羟基苯基]-乙基-氨基甲基）四氢萘酮结合的放射性配体测定蛋白质表达（总α 1 AR密度的饱和分析和与BMY7378和5-methylurapidel的竞争分析，以确定α 1 AR亚型）。结果在该模型中，6周的手术梗阻使膀胱重量比假手术增加6.3倍（p <0.001），同时排尿频率比梗阻前增加（p <0.004）。虽然膀胱α 1 AR密度总体上没有随着梗阻而增加，但α 1 AR亚型表达发生了显著变化。在对照组动物中，70%的alpha1AR mRNA为alpha1a亚型，5%为alpha1b亚型，25%为alpha1d亚型，而在梗阻动物膀胱中，alpha1AR表达变为23%的alpha1a亚型，2%的alpha1b亚型和75%的alpha1d亚型。在整个膀胱顶，中间体和基地的α 1 AR mRNA表达的变化幅度相似。在蛋白质水平上也存在明显的平行变化，对照动物中100%的alpha1aAR表达变为膀胱重量增加5倍或以上的动物中新发alpha1dAR表达（平均值±平均值的标准误差为36% ± 7%）。结论：我们的研究结果表明梗阻6周后膀胱alpha1 dAR mRNA和蛋白表达显著增加，并导致逼尿肌肥大。这一发现可能很重要，因为alpha1dAR对内源性神经递质去甲肾上腺素的亲和力比alpha1a或alpha1bAR亚型高10至100倍。这些发现意味着，针对alpha1d可能提供一种新的治疗方法，用于控制膀胱刺激症状和可能与膀胱出口梗阻相关的逼尿肌过度活动。
PURPOSE alpha1-Adrenergic receptor (alpha1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the alpha1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder alpha1AR subtypes may be involved in this process. MATERIALS AND METHODS We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. alpha1AR subtype messenger (m)RNA was quantitated using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the alpha1AR antagonist [125iodine]2-(-[4-hydroxyphenyl]-ethyl-aminomethyl)tetralone (saturation analysis for total alpha1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine alpha1AR subtypes). RESULTS In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder alpha1AR density did not increase overall with obstruction, striking changes in alpha1AR subtype expression occurred. In control animals 70% of alpha1AR mRNA was the alpha1a subtype, 5% were alpha1b and 25% were alpha1d, whereas in obstructed animals bladder alpha1AR expression changed to 23% alpha1a, 2% alpha1b and 75% alpha1d. Changes in alpha1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% alpha1aAR expression in control animals changing to new onset alpha1dAR expression (mean plus or minus standard error of mean 36% +/- 7%) in animals with a 5-fold or greater increase in bladder weight. CONCLUSIONS Our findings indicate a remarkable increase in bladder alpha1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since alpha1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the alpha1a or alpha1bAR subtypes. These findings imply that targeting alpha1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.