Kim S H, Cho K W, Chang S H, Kim S Z, Chae S W
Department of Physiology, Jeonbug National University, Medical School, Institute for Medical Sciences, 2-20, Keum-Am-Dong-San, Jeonju 560-180, Republic of Korea.
Pflugers Arch. 1997 Aug;434(4):362-72. doi: 10.1007/s004240050409.
The mechanism by which glibenclamide regulates mechanically activated atrial natriuretic peptide (ANP) secretion was investigated using isolated perfused rat atria. A reduction in atrial pressure from an experimentally imposed distending pressure stimulated the secretion of ANP and caused concomitant translocation of extracellular fluid (ECF) into the atrial lumen. The activation of ANP secretion and ECF translocation were closely correlated with atrial volume changes and the increase in ANP secretion was a function of the ECF translocation. Glibenclamide (1, 10, 100 microM), an ATP-sensitive K+ (K+ATP) channel blocker, had no effect on the basal secretion of ANP, suppressed the stimulation of stretch-activated ANP secretion in a dose-dependent manner, but not the translocation of the ECF. Glipizide (100 microM) and tolbutamide (100 microM), other K+ATP channel blockers, had similar effects to those of glibenclamide. Suppression by glibenclamide (100 microM) of the stretch-induced ANP secretion was not observed in atria that had been pretreated with pinacidil (200 microM), an ATP-sensitive K+ channel opener: pinacidil alone had no effect on ECF translocation and ANP secretion. Furthermore, blocking Ca2+ influx by using the Ca2+ channel blocker diltiazem (10 nM), or a Ca2+-depleted medium prevented the suppression of stretch-induced ANP secretion by glibenclamide. In other experiments, atrial distension produced a slight membrane depolarization of cardiomyocytes; this was accentuated in the presence of glibenclamide. Furthermore, in single cardiomyocytes, glibenclamide increased the intracellular Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. From these results, we suggest that glibenclamide suppresses atrial release of ANP by blocking K+ATP channels and increasing Ca2+ influx and that the K+ATP channels are associated with the regulation of the mechanically activated ANP secretion from the atria.
使用离体灌注大鼠心房研究了格列本脲调节机械激活的心房利钠肽（ANP）分泌的机制。将心房压力从实验施加的扩张压力降低会刺激ANP分泌，并导致细胞外液（ECF）同时转移到心房腔中。ANP分泌的激活和ECF转移与心房容积变化密切相关，且ANP分泌的增加是ECF转移的函数。格列本脲（1、10、100微摩尔），一种ATP敏感性钾（K+ATP）通道阻滞剂，对ANP的基础分泌无影响，以剂量依赖性方式抑制牵张激活的ANP分泌，但不影响ECF转移。其他K+ATP通道阻滞剂格列吡嗪（100微摩尔）和甲苯磺丁脲（100微摩尔）具有与格列本脲类似的作用。在已用ATP敏感性钾通道开放剂吡那地尔（200微摩尔）预处理的心房中未观察到格列本脲（100微摩尔）对牵张诱导的ANP分泌的抑制作用：单独使用吡那地尔对ECF转移和ANP分泌无影响。此外，使用钙通道阻滞剂地尔硫䓬（10纳摩尔）或无钙培养基阻断Ca2+内流可防止格列本脲抑制牵张诱导的ANP分泌。在其他实验中，心房扩张使心肌细胞产生轻微的膜去极化；在格列本脲存在的情况下这种去极化会加剧。此外，在单个心肌细胞中，格列本脲以剂量依赖性方式增加细胞内Ca2+浓度（[Ca2+]i）。根据这些结果，我们认为格列本脲通过阻断K+ATP通道和增加Ca2+内流来抑制心房释放ANP，并且K+ATP通道与心房机械激活的ANP分泌调节有关。
