Xiao Jian-Feng, Wang Chun-Yan, Huang Yong-Pan, Shen Jian-Xin, Gao Fen-Fei, Huang Zhan-Qin, Zheng Yan-Shan, Shi Gang-Gang
Department of Pharmacology, Shantou University Medical College, 22 Xinling Road, Shantou, PR China.
Cell Physiol Biochem. 2011;27(5):433-42. doi: 10.1159/000329964. Epub 2011 Jun 15.
N-n-Butyl haloperidol iodide (F(2)) is a novel compound derived from haloperidol. In our previous work, F(2) was found to be an L-type calcium channel blocker which played a protective role in rat heart ischemic-reperfusion injury in a dose-dependent manner. In the current study, we aimed to investigate the effects and some possible mechanisms of F(2) on calcium transients in hypoxic/ischemic rat cardiac myocytes.
Calcium transients' images of rat cardiac myocytes were recorded during simulated hypoxia, using a confocal calcium imaging system. The amplitude, rising time from 25% to 75% (RT25-75), decay time from 75% to 25% (DT75-25) of calcium transients, and resting Ca(2+) were extracted from the images by self-coding programs. In this study, hypoxia produced a substantial increase in diastolic Ca(2+) and reduced the amplitude of calcium transients. Both RT25-75 and DT75-25 of Ca(2+) transients were significantly prolonged. And F(2) could reduce the increase in resting Ca(2+)and the prolongation of RT25-75 and DT75-25 of Ca(2+) transients during hypoxia. F(2) also inhibited the reduction in amplitude of calcium transients which was caused by 30-min hypoxia. The activity of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase, determined by test kits) decreased after 30-min ischemia, and intravenous F(2) in rats could ameliorate the decreased activity of SERCA2a. The inward and outward currents of NCX (recorded by whole-cell patch-clamp analysis) were reduced during 10-min hypoxia, and F(2) further inhibited the outward currents of NCX during 10-min hypoxia. All these data of SERCA2a and NCX might be responsible for the changes in calcium transients during hypoxia.
Our data suggest that F(2) reduced changes in calcium transients that caused by hypoxia/ischemia, which was regarded to be a protective role in calcium homeostasis of ventricular myocytes, probably via changing the function of SERCA2a.
碘化N-正丁基氟哌啶醇（F(2)）是一种从氟哌啶醇衍生而来的新型化合物。在我们之前的研究中，发现F(2)是一种L型钙通道阻滞剂，对大鼠心脏缺血再灌注损伤具有剂量依赖性的保护作用。在本研究中，我们旨在探讨F(2)对缺氧/缺血大鼠心肌细胞钙瞬变的影响及一些可能机制。
使用共聚焦钙成像系统记录模拟缺氧过程中大鼠心肌细胞的钙瞬变图像。通过自编程序从图像中提取钙瞬变的幅度、从25%上升到75%的时间（RT25-75）、从75%衰减到25%的时间（DT75-25）以及静息[Ca(2+)]i。在本研究中，缺氧导致舒张期[Ca(2+)]i大幅增加，并降低了钙瞬变的幅度。Ca(2+)瞬变的RT25-75和DT75-25均显著延长。并且F(2)可以减少缺氧期间静息[Ca(2+)]i的增加以及Ca(2+)瞬变的RT25-75和DT75-25的延长。F(2)还抑制了由30分钟缺氧引起的钙瞬变幅度的降低。30分钟缺血后，SERCA2a（肌浆网Ca(2+)-ATP酶，通过试剂盒测定）的活性降低，大鼠静脉注射F(2)可改善SERCA2a活性的降低。在10分钟缺氧期间，NCX的内向和外向电流（通过全细胞膜片钳分析记录）降低，F(2)在10分钟缺氧期间进一步抑制了NCX的外向电流。SERCA2a和NCX的所有这些数据可能是缺氧期间钙瞬变变化的原因。
我们的数据表明，F(2)减少了缺氧/缺血引起的钙瞬变变化，这被认为对心室肌细胞钙稳态具有保护作用，可能是通过改变SERCA2a的功能实现的。
