Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas (SP), Brazil.
Eur J Pharmacol. 2010 Jul 10;637(1-3):171-7. doi: 10.1016/j.ejphar.2010.04.008. Epub 2010 Apr 23.
The nitric oxide (NO)-independent soluble guanylyl cyclase stimulator stimulator BAY 41-2272 was reported to produce relaxant response in different types of smooth muscle. However no study was carried out to investigate the effects of BAY 412282 in detrusor smooth muscle. Thus, this study aimed to evaluate the relaxant effects of BAY 41-2272, in isolated mouse, rat and rabbit detrusor smooth muscle. Mouse, rat and rabbit were anesthetized, and urinary bladder removed. Detrusor smooth muscle was transferred to 10-mL organ baths containing oxygenated and warmed Krebs-Henseleit solution. Tissues were connected to force-displacement transducers and changes in isometric force were recorded. BAY 41-2272 (0.001-100 microM) produced concentration-dependent detrusor smooth muscle relaxations in mouse, rat and rabbit with maximal responses of 61.3+/-6.6%, 95.1+/-9.9% and 91.7+/-5.9%, respectively. Sodium nitroprusside and glyceryl trinitrate, as well as 8-bromo-cGMP also produced detrusor relaxations, but to a much lesser extent than BAY 41-2272. The NO synthesis inhibitor L-NAME and the phosphodiesterase-5 inhibitor sildenafil had no effect in BAY 41-2272-induced responses. However, the soluble guanylyl cyclase inhibitor ODQ significantly reduced BAY 41-2272-induced relaxations. BAY 41-2272 increased the bladder cGMP levels by about of 14- and 20-fold for 10 and 100 microM, respectively, which were markedly reduced by ODQ. The cAMP levels were unaffected by BAY 41-2272. Moreover, BAY 41-2272 significantly reduced the contractile responses to extracellular Ca(2+) in an ODQ-insensitive manner. In conclusion, rabbit detrusor smooth muscle relaxations by BAY 41-2272 involve mainly cGMP production, but an additional mechanism involving Ca(2+) influx blockade independently of cGMP production appears to be involved.
一氧化氮（NO）-非依赖性可溶性鸟苷酸环化酶刺激剂刺激剂 BAY 41-2272 据报道可在不同类型的平滑肌中产生舒张反应。然而，没有研究探讨 BAY 412282 在逼尿肌平滑肌中的作用。因此，本研究旨在评估 BAY 41-2272 对离体小鼠、大鼠和兔逼尿肌平滑肌的舒张作用。将小鼠、大鼠和兔麻醉，取出膀胱。将逼尿肌平滑肌转移至含有氧合和加热的 Krebs-Henseleit 溶液的 10-mL 器官浴中。组织与力位移换能器相连，记录等长力的变化。BAY 41-2272（0.001-100 microM）在小鼠、大鼠和兔逼尿肌中产生浓度依赖性舒张反应，最大反应分别为 61.3+/-6.6%、95.1+/-9.9%和 91.7+/-5.9%。硝普钠和甘油三硝酸酯以及 8-溴-cGMP 也产生逼尿肌松弛，但程度远低于 BAY 41-2272。NO 合成抑制剂 L-NAME 和磷酸二酯酶-5 抑制剂西地那非对 BAY 41-2272 诱导的反应没有影响。然而，可溶性鸟苷酸环化酶抑制剂 ODQ 显著降低了 BAY 41-2272 诱导的松弛。BAY 41-2272 使 10 和 100 microM 时膀胱 cGMP 水平分别增加约 14 倍和 20 倍，而 ODQ 显著降低了 cGMP 水平。BAY 41-2272 对 cAMP 水平没有影响。此外，BAY 41-2272 以 ODQ 不敏感的方式显著降低了细胞外 Ca(2+)引起的收缩反应。总之，BAY 41-2272 引起的兔逼尿肌松弛主要涉及 cGMP 的产生，但还涉及一种独立于 cGMP 产生的涉及 Ca(2+)内流阻断的附加机制。
