Shenfeld O Z, Morgan C W, Ratz P H
Department of Urology, Eastern Virginia Medical School, Norfolk 23501, USA.
J Urol. 1998 Jan;159(1):252-7. doi: 10.1016/s0022-5347(01)64077-1.
Recent studies using vascular and gut smooth muscles indicate that contractile receptor agonists may activate post-receptor down-regulatory mechanisms causing a temporary reduction in the strength of subsequent contractions. Our data indicate a similar mechanism exists in detrusor smooth muscle of the urinary bladder.
Each isolated strip of female rabbit detrusor was placed in a tissue bath, secured to an isometric force transducer, and length-adjusted until depolarization with 110 mM KCl produced a maximum contraction (S0). Subsequent contractions were normalized to S0 (S/S0) or to a first stimulus with 30 mM KCl or caffeine (S/S1). Tissues were pretreated with the muscarinic receptor agonist, bethanechol (BE), then stimulated with KCl, caffeine, or Bay k 8644 to identify potential post-receptor down-regulation.
Contractions induced by 30 mM KCl had three phases labeled fast peak (FP), slow peak (SP) and steady-state (SS). In tissues exposed for 30 min. to a maximum BE concentration then washed for 5 min., the KCl-induced FP and SP, but not SS, responses were reduced by approximately 40%. Smaller reductions in peak KCl-induced contractions occurred in tissues pretreated for a shorter duration or with a 100-fold lower BE concentration. This down-regulation induced by bethanechol pretreatment was reversible, lasting approximately 1-2 h. Not only were KCl-induced contractions reduced by BE pretreatment, but also those produced by the intracellular Ca(2+)-mobilizer, caffeine, and the L-type Ca2+ channel agonist, Bay k 8644.
Pretreatment of isolated strips of rabbit detrusor with a muscarinic receptor agonist produced short-term down-regulation of KCl-induced peak contractions that may have involved inhibition of both influx of extracellular Ca2+ and release of intracellular Ca2+. Reductions in the degree of this novel modulatory response during disease conditions and aging could enhance contractile activity, possibly causing detrusor instability.
近期使用血管和平滑肌的研究表明，收缩性受体激动剂可能激活受体后下调机制，导致随后收缩强度暂时降低。我们的数据表明，膀胱逼尿肌中存在类似机制。
将每条雌性兔逼尿肌分离条置于组织浴中，固定在等长力换能器上，并调整长度，直至用110 mM氯化钾去极化产生最大收缩（S0）。随后的收缩以S0（S/S0）或用30 mM氯化钾或咖啡因的第一次刺激（S/S1）进行标准化。用毒蕈碱受体激动剂氨甲酰甲胆碱（BE）预处理组织，然后用氯化钾、咖啡因或Bay k 8644刺激，以确定潜在的受体后下调。
30 mM氯化钾诱导的收缩有三个阶段，分别标记为快速峰值（FP）、缓慢峰值（SP）和稳态（SS）。在暴露于最大BE浓度30分钟然后冲洗5分钟的组织中，氯化钾诱导的FP和SP反应，但不是SS反应，降低了约40%。在预处理时间较短或BE浓度低100倍的组织中，氯化钾诱导的峰值收缩减少较小。氨甲酰甲胆碱预处理诱导的这种下调是可逆的，持续约1-2小时。不仅氯化钾诱导的收缩因BE预处理而减少，细胞内钙动员剂咖啡因和L型钙通道激动剂Bay k 8644诱导的收缩也减少。
用毒蕈碱受体激动剂预处理兔逼尿肌分离条，可使氯化钾诱导的峰值收缩产生短期下调，这可能涉及抑制细胞外钙内流和细胞内钙释放。在疾病状态和衰老过程中，这种新型调节反应程度的降低可能会增强收缩活性，可能导致逼尿肌不稳定。
