Zhang Zhenjie, Klyachko Vitaly, Jackson Meyer B
Department of Physiology, University of Wisconsin, Madison WI, USA.
J Physiol. 2007 Oct 1;584(Pt 1):137-47. doi: 10.1113/jphysiol.2007.139303. Epub 2007 Aug 9.
Phosphodiesterase type 5 (PDE5) acts specifically on cyclic guanosine monophosphate (cGMP) and terminates cGMP-mediated signalling. PDE5 has a well established role in vascular smooth muscle, where specific inhibitors of PDE5 such as sildenafil correct erectile dysfunction by augmenting cGMP-mediated vascular relaxation. However, the role of PDE5 outside of the vasculature has received little attention. The present study tested PDE5 inhibitors on the cGMP-mediated modulation of K(+) channels in the neurohypophysis (posterior pituitary). Photolysis of caged-cGMP enhanced current through Ca(2+)-activated K(+) channels, and this enhancement recovered in about 2 min. Sildenafil essentially eliminated this recovery, suggesting that the reversal of K(+) current enhancement depends on cGMP breakdown. Activation of nitric oxide synthase during trains of activity in pituitary nerve terminals enhances excitability. When trains of stimulation were applied at regular intervals, sildenafil enhanced the excitability of neurohypophysial nerve terminals and increased the action potential firing probability. T-1032, a compound with high specificity for PDE5 over PDE6, had a similar action. Voltage imaging in intact neurohypophysis with a voltage sensitive absorbance dye showed that T-1032 reduced the failure of propagating action potentials during trains of activity. This indicates that PDE5 activity limits action potential propagation in neurohypophysial axons. Immunoassay of oxytocin, a neuropeptide hormone secreted by the posterior pituitary, demonstrated that sildenafil increased electrically evoked release. Thus, PDE5 plays an important role in the regulation of neurohypophysial function, and blockade of this enzyme can enhance the use-dependent facilitation of neurohypophysial secretion.
5型磷酸二酯酶(PDE5)特异性作用于环磷酸鸟苷(cGMP),并终止cGMP介导的信号传导。PDE5在血管平滑肌中具有明确的作用,PDE5的特异性抑制剂如西地那非可通过增强cGMP介导的血管舒张来纠正勃起功能障碍。然而,PDE5在脉管系统之外的作用很少受到关注。本研究测试了PDE5抑制剂对神经垂体(垂体后叶)中cGMP介导的钾通道调节作用。笼装cGMP的光解增强了通过钙激活钾通道的电流,这种增强在约2分钟内恢复。西地那非基本上消除了这种恢复,表明钾电流增强的逆转依赖于cGMP的分解。垂体神经末梢活动串期间一氧化氮合酶的激活增强了兴奋性。当以规则间隔施加刺激串时,西地那非增强了神经垂体神经末梢的兴奋性并增加了动作电位发放概率。T-1032是一种对PDE5比对PDE6具有高特异性的化合物,具有类似作用。用电压敏感吸收染料对完整神经垂体进行电压成像显示,T-1032减少了活动串期间动作电位传播的失败。这表明PDE5活性限制了神经垂体轴突中动作电位的传播。对垂体后叶分泌的神经肽激素催产素的免疫测定表明,西地那非增加了电诱发释放。因此,PDE5在神经垂体功能调节中起重要作用,阻断该酶可增强神经垂体分泌的使用依赖性易化作用。