Yamazaki J, Hume J R
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno 89557-0046, USA.
Circ Res. 1997 Jul;81(1):101-9. doi: 10.1161/01.res.81.1.101.
Recent studies have provided evidence that sulfonylureas, in addition to blocking ATP-sensitive K+ (KATP) channels, also inhibit cystic fibrosis transmembrane regulator (CFTR) Cl- channels in epithelial and cardiac cells. The purpose of this study was to test whether the sulfonylurea glibenclamide might also inhibit other types of cardiac Cl- channels. Whole-cell patch-clamp techniques were used to compare the effects of glibenclamide on CFTR Cl- currents in guinea pig ventricular myocytes, swelling-activated Cl- currents in guinea pig atrial myocytes, and Ca(2+)-activated Cl- currents in canine ventricular myocytes. Glibenclamide markedly inhibited CFTR Cl- currents in a voltage-independent manner at 22 degrees C, with estimated IC50 values of 12.5 and 11.0 mumol/L at +50 and -100 mV, respectively. The outwardly rectifying swelling-activated Cl- current in atrial cells was less sensitive to glibenclamide, and the block exhibited voltage dependence. At 22 degrees C, the estimated IC50 values were 193 and 470 mumol/L at +50 and -100 mV, respectively, and block was enhanced at 35 degrees C. Macroscopic Cl- currents activated by a rise in intracellular Ca2+, induced by either Ca(2+)-induced Ca2+ release or by external application of the Ca2+ ionophore A23187, were also markedly inhibited at 22 degrees C by glibenclamide in a voltage-independent manner. The estimated IC50 values were 61.5 and 69.9 mumol/L at +50 and -100 mV, respectively. These results suggest that glibenclamide, an inhibitor of cardiac CFTR Cl- channels, also inhibits swelling-activated and Ca(2+)-activated Cl- channels at higher concentrations. The results also suggest that studies attributing the beneficial or deleterious effects of sulfonylurea compounds in the heart solely to blockade of KATP channels should use submicromolar concentrations of these agents to minimize possible secondary interactions with cardiac Cl- channels.
最近的研究表明，磺脲类药物除了阻断ATP敏感性钾离子（KATP）通道外，还能抑制上皮细胞和心肌细胞中的囊性纤维化跨膜传导调节因子（CFTR）氯离子通道。本研究旨在测试磺脲类药物格列本脲是否也能抑制其他类型的心肌氯离子通道。采用全细胞膜片钳技术比较格列本脲对豚鼠心室肌细胞中CFTR氯离子电流、豚鼠心房肌细胞中肿胀激活氯离子电流以及犬心室肌细胞中钙激活氯离子电流的影响。在22℃时，格列本脲以电压非依赖性方式显著抑制CFTR氯离子电流，在+50mV和-100mV时，估计的半数抑制浓度（IC50）值分别为12.5和11.0μmol/L。心房细胞中向外整流的肿胀激活氯离子电流对格列本脲的敏感性较低，且阻断表现出电压依赖性。在22℃时，在+50mV和-100mV时，估计的IC50值分别为193和470μmol/L，在35℃时阻断作用增强。由钙诱导的钙释放或外部应用钙离子载体A23187诱导的细胞内钙离子升高激活的宏观氯离子电流，在22℃时也被格列本脲以电压非依赖性方式显著抑制。在+50mV和-100mV时，估计的IC50值分别为61.5和69.9μmol/L。这些结果表明，作为心肌CFTR氯离子通道抑制剂的格列本脲，在较高浓度时也能抑制肿胀激活和钙激活的氯离子通道。结果还表明，将磺脲类化合物在心脏中的有益或有害作用仅归因于对KATP通道的阻断的研究，应使用亚微摩尔浓度的这些药物，以尽量减少与心肌氯离子通道可能的二次相互作用。
