Depts. of Pharmacology and Pharmacotherapy and of Urology, Academic Medical Center, Amsterdam, The Netherlands.
Naunyn Schmiedebergs Arch Pharmacol. 2011 Dec;384(6):555-63. doi: 10.1007/s00210-011-0689-8. Epub 2011 Sep 24.
β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M(3)-sparing muscarinic agonist, providing selective M(2) stimulation in rat bladder, and THRX-182087 as a highly M(2)-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M(2) or M(3) receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M(2)-selective stimulation partly mimicked this attenuation, indicating that both M(2) and M(3) receptors are involved. During M(3)-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M(2) and M(3) receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M(3) component of this attenuation differs from that mediating direct contractile effects of M(3) receptors.
β-肾上腺素受体是膀胱平滑肌松弛的重要介质，但同时存在毒蕈碱激动剂（如卡巴胆碱）时，可通过降低β-肾上腺素受体激动剂（如异丙肾上腺素）的效力和/或效能来减弱松弛反应。因此，本研究旨在探讨参与异丙肾上腺素诱导的离体大鼠膀胱制剂松弛的毒蕈碱受体亚型和信号通路，使用新型亚型选择性受体配体。在放射性配体结合研究中，我们将 BZI 鉴定为 M(3)-选择性毒蕈碱激动剂，在大鼠膀胱中提供选择性 M(2)刺激，而 THRX-182087 则为高度 M(2)-选择性拮抗剂。在卡巴胆碱存在的情况下使用 BZI 和 THRX-182087，可以分别实现仅选择性刺激 M(2)或 M(3)受体的实验条件。证实了先前的发现，即卡巴胆碱减弱了异丙肾上腺素诱导的膀胱松弛。M(2)-选择性刺激部分模拟了这种衰减，表明 M(2)和 M(3)受体都参与其中。在 M(3)-选择性刺激期间，使用磷脂酶 C 抑制剂 U 73,122 减弱了异丙肾上腺素反应的衰减，但使用蛋白激酶 C 抑制剂 chelerythrine 则没有。我们得出结论，M(2)和 M(3)受体都有助于减弱大鼠膀胱β-肾上腺素受体介导的松弛；涉及这种衰减的 M(3)成分的信号转导通路与介导 M(3)受体直接收缩作用的信号转导通路不同。
