Yunoki Takakazu, Zhu Hai-Lei, Iwasa Kazuomi, Tomoda Toshihisa, Aishima Manami, Shibata Atsushi, Naito Seiji, Teramoto Noriyoshi
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi Ward, Fukuoka 812-8582, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jan;376(5):309-19. doi: 10.1007/s00210-007-0241-z. Epub 2007 Dec 11.
The effects of ZD0947, a novel urinary bladder selective ATP-sensitive potassium channel (K(ATP) channel) opener, on carbachol-induced contractions of isolated guinea pig urinary bladder strips were investigated to compare its ability to relax norepinephrine-induced contraction of the aorta. Electrophysiological techniques were also utilized to compare the effects of ZD0947 on membrane currents between guinea pig detrusor and aortic myocytes. ZD0947 caused a significant reduction of the carbachol-induced contractile activity, demonstrating a biphasic relaxation (the first and second components). Although glibenclamide antagonized the effects of two components for the ZD0947-induced relaxation, gliclazide, a selective sulphonylurea receptor 1 (SUR1) antagonist, reduced the effects of the first component but not the second component of the ZD0947-induced relaxation. ZD0947 also reduced the norepinephrine-induced contraction of the aorta. ZD0947 reduced electrical excitability of detrusor smooth muscles, inhibiting spike discharges and also hyperpolarizing the membrane as measured with microelectrodes. In conventional whole-cell configuration, ZD0947 caused a glibenclamide-sensitive K(+) current (i.e., K(ATP) current) at a holding potential of -60 mV in guinea pig detrusor and aortic myocytes. The current density of ZD0947-induced K(ATP) currents in guinea pig detrusor myocytes was significantly larger than that in aortic smooth muscle cells. These results show that ZD0947 caused a significant relaxation through the activation of K(ATP) channels in detrusor muscle.
研究了新型膀胱选择性ATP敏感性钾通道（K(ATP)通道）开放剂ZD0947对卡巴胆碱诱导的豚鼠离体膀胱条收缩的影响，以比较其舒张去甲肾上腺素诱导的主动脉收缩的能力。还利用电生理技术比较ZD0947对豚鼠逼尿肌和主动脉肌细胞膜电流的影响。ZD0947显著降低了卡巴胆碱诱导的收缩活性，表现出双相舒张（第一和第二成分）。尽管格列本脲拮抗了ZD0947诱导舒张的两个成分的作用，但选择性磺酰脲受体1（SUR1）拮抗剂格列齐特降低了ZD0947诱导舒张的第一成分的作用，但未降低第二成分的作用。ZD0947也降低了去甲肾上腺素诱导的主动脉收缩。ZD0947降低了逼尿肌平滑肌的电兴奋性，抑制了动作电位发放，并用微电极测量发现其使细胞膜超极化。在传统的全细胞模式下，ZD0947在豚鼠逼尿肌和主动脉肌细胞中于-60 mV的钳制电位下引起一种格列本脲敏感的K(+)电流（即K(ATP)电流）。ZD0947诱导的豚鼠逼尿肌细胞中K(ATP)电流的电流密度显著大于主动脉平滑肌细胞中的电流密度。这些结果表明，ZD0947通过激活逼尿肌中的K(ATP)通道引起显著的舒张。
