Institute of Pharmacology, School of Medicine, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168 Rome, Italy.
Pharmacol Res. 2011 Oct;64(4):397-409. doi: 10.1016/j.phrs.2011.06.016. Epub 2011 Jun 28.
Voltage-dependent type 7 K+ (KV7) channels play important physiological roles in neurons and muscle cells. The aims of the present study were to investigate the motor effects of KV7 channel modulators in the rat gastric fundus and the expression of KV7 channels in this tissue. Muscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal muscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions by organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels was investigated by immunohistochemistry. The KV7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD2 and Emax of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The KV7 channel activators retigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD2s of 4.7 and 4.4 and Emax of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991 concentration-dependently inhibited retigabine-induced relaxation with a pIC50 of 6.2. XE-991 and DMP-543, another KV7 channel blocker, increased by 13-25% or reduced by 11-21% the relaxations evoked by low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive intestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all KV7 genes were detected in the fundus, with 7.4 and 7.5 showing the highest expression levels. KV7.4 and 7.5 channels were visualized by confocal immunofluorescence in both circular and longitudinal muscle layers. In conclusion, in the rat proximal stomach, KV7 channels appear to contribute to the resting muscle tone and to VIP- and high-frequency EFS-induced relaxation. KV7 channel activators could be useful relaxant agents of the gastric smooth muscle.
电压门控型 7 钾 (KV7) 通道在神经元和肌肉细胞中发挥着重要的生理作用。本研究旨在探讨 KV7 通道调节剂在大鼠胃底的运动效应以及该组织中 KV7 通道的表达。通过器官浴研究，在非肾上腺素非胆碱能条件下，研究大鼠胃底纵向肌条预收缩时的肌肉张力和电刺激 (EFS) 诱发的松弛作用。通过实时 PCR 研究基因表达，通过免疫组织化学研究通道的组织定位。KV7 通道阻滞剂 XE-991 诱导浓度依赖性收缩，其平均 pD2 和 Emax 分别为 U46619 诱导收缩的 48%和 5.4%。KV7 通道激活剂 retigabine 和 flupirtine 浓度依赖性地松弛 U46619 预收缩的条带，其 pD2 分别为 4.7 和 4.4，最大罂粟碱诱导的松弛度分别为 93%和 91%。XE-991 浓度依赖性地抑制 retigabine 诱导的松弛，pIC50 为 6.2。XE-991 和 DMP-543（另一种 KV7 通道阻滞剂）分别增加或减少低频率或高频率 EFS 引起的松弛 13-25%或 11-21%。XE-991 还使 VIP 诱导的松弛减少 33%。在胃底检测到所有 KV7 基因编码的转录本，7.4 和 7.5 的表达水平最高。在环形和纵向肌肉层中，通过共聚焦免疫荧光观察到 KV7.4 和 7.5 通道。总之，在大鼠近端胃中，KV7 通道似乎有助于静息肌肉张力和 VIP 和高频 EFS 诱导的松弛。KV7 通道激活剂可能是胃平滑肌松弛的有用药物。
