Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Neurourol Urodyn. 2012 Jun;31(5):688-94. doi: 10.1002/nau.22203. Epub 2012 Mar 27.
The involvement of endothelin receptors in the contraction of the lower urinary tract smooth muscle is well established. There is scarce information, however, about endothelin receptors mediating relaxation of the bladder outlet region. The current study investigates the possible existence of endothelin ET(B) receptors involved in the relaxation of pig bladder neck.
ET(B) receptor expression was determined by immunohistochemistry and urothelium-denuded bladder neck strips were mounted in organ baths for isometric force recording.
ET(B) -immunoreactivity (ET(B) -IR) was observed within nerve fibers among smooth muscle bundles and urothelium. BQ3020 (0.01-300 nM), an ET(B) receptor agonist, produced concentration-dependent relaxations which were reduced by BQ788, an ET(B) receptor antagonist, and by inhibitors of protein kinase A (PKA) and large (BK(Ca) )- or small (SK(Ca) )-conductance Ca(2+) -activated K(+) channels. Pretreatment with BK(Ca) or SK(Ca) channel inhibitors plus PKA blocking did not cause further inhibition compared with that exerted by inhibiting BK(Ca) or SK(Ca) channels only. BQ3020-induced relaxation was not modified by blockade of either nitric oxide (NO) synthase, guanylyl cyclase, cyclooxygenase (COX) or of intermediate-conductance Ca(2+) -activated-(IK(Ca) ), ATP-dependent-(K(ATP) ), or voltage-gated-(K(v) ) K(+) channels. Under non-adrenergic non-cholinergic (NANC) conditions, electrical field stimulation (0.5-16 Hz) evoked frequency-dependent relaxations, which were reduced by BQ788 and potentiated by threshold concentrations of BQ3020.
These results suggest that BQ3020 produces relaxation of the pig bladder neck via activation of muscle endothelin ET(B) receptors, NO/cGMP- and COX-independent-, cAMP-PKA pathway-dependent-mechanisms, and involving BK(Ca) and SK(Ca) channel activation. ET(B) receptors are also involved in the NANC inhibitory neurotransmission.
内皮素受体参与下尿路平滑肌收缩的作用已得到充分证实。然而，关于内皮素受体介导膀胱出口区域松弛的信息却很少。本研究旨在探讨参与猪膀胱颈部松弛的内皮素 ET(B)受体的可能存在。
通过免疫组织化学确定 ET(B)受体的表达，并将去上皮的膀胱颈部条带安装在器官浴中进行等长力记录。
在平滑肌束和尿路上皮之间的神经纤维中观察到内皮素 ET(B)受体免疫反应性（ET(B) -IR）。ET(B)受体激动剂 BQ3020（0.01-300 nM）产生浓度依赖性松弛，这种松弛被 ET(B)受体拮抗剂 BQ788 和蛋白激酶 A（PKA）抑制剂以及大电导（BK(Ca)）或小电导（SK(Ca)）钙激活钾（K(Ca)）通道抑制剂所抑制。与仅抑制 BK(Ca) 或 SK(Ca) 通道相比，预先用 BK(Ca) 或 SK(Ca) 通道抑制剂加 PKA 阻断处理不会导致进一步的抑制。NO 合酶、鸟苷酸环化酶、环氧化酶（COX）、中间电导钙激活（IK(Ca)）、ATP 依赖性（K(ATP)）或电压门控（K(v)）K(+)通道的阻断均不改变 BQ3020 诱导的松弛。在非肾上腺素能非胆碱能（NANC）条件下，电刺激（0.5-16 Hz）诱发频率依赖性松弛，这种松弛被 BQ788 抑制，阈浓度的 BQ3020 增强。
这些结果表明，BQ3020 通过激活肌肉内皮素 ET(B)受体产生猪膀胱颈部的松弛，该过程与 NO/cGMP-和 COX-非依赖性、cAMP-PKA 通路依赖性机制有关，涉及 BK(Ca) 和 SK(Ca) 通道的激活。ET(B)受体也参与 NANC 抑制性神经传递。
