Yuan X J, Tod M L, Rubin L J, Blaustein M P
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Exp Physiol. 1995 Sep;80(5):803-13. doi: 10.1113/expphysiol.1995.sp003888.
Inhibition of voltage-gated K+ (Kv) channels by 4-aminopyridine (4-AP) depolarizes pulmonary artery (PA) smooth muscle cells, induces Ca(2+)-dependent action potentials and increases [Ca2+]i. Neither charybdotoxin, which blocks Ca(2+)-activated K+ channels, nor glibenclamide, which blocks ATP-sensitive K+ channels, has such effects on membrane potential (Em) and [Ca2+]i. Hypoxia reversibly decreases the 4-AP-sensitive KV currents (IK(V)) in PA myocytes. The resulting membrane depolarization caused by decreased IK(V) induces Ca(2+)-dependent action potentials and thereby raises [Ca2+]i. Thus, KV channel activity plays a critical role in: (a) regulating Em and [Ca2+]i under physiological conditions; and (b) sensing O2 alteration and transducing the hypoxic stimulus to changes of Em and [Ca2+]i. The metabolic inhibitors 2-deoxy-D-glucose (2-DOG; 10 mM) and carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP; 3-5 microM), the reducing agent reduced glutathione and inhibitors of cytochrome P-450, all mimic the effects of hypoxia on IK(V) and Em in PA myocytes. Furthermore, hypoxia and 2-DOG negligibly affect IK(V) and Em in mesenteric artery smooth muscle cells. These results suggest that hypoxia, perhaps via a localized reduction of ATP, triggers the block of KV channels and depolarizes PA myocytes. This blockade may also be mediated by a change in cellular redox status, perhaps via a conformational change of a haem- (or metal-) containing regulatory moiety that is attached to the channel protein.
4-氨基吡啶（4-AP）对电压门控性钾离子（Kv）通道的抑制作用可使肺动脉（PA）平滑肌细胞发生去极化，诱导钙依赖性动作电位并增加细胞内钙离子浓度（[Ca2+]i）。阻断钙激活钾通道的蝎毒素和阻断ATP敏感性钾通道的格列本脲，对膜电位（Em）和[Ca2+]i均无此类作用。低氧可使PA肌细胞中对4-AP敏感的钾电流（IK(V)）可逆性降低。IK(V)降低导致的膜去极化可诱导钙依赖性动作电位，从而升高[Ca2+]i。因此，Kv通道活性在以下方面起关键作用：（a）在生理条件下调节Em和[Ca2+]i；（b）感知氧的变化并将低氧刺激转化为Em和[Ca2+]i的变化。代谢抑制剂2-脱氧-D-葡萄糖（2-DOG；10 mM）、羰基氰-对-三氟甲氧基苯腙（FCCP；3 - 5 microM）、还原剂还原型谷胱甘肽以及细胞色素P-450抑制剂，均模拟低氧对PA肌细胞IK(V)和Em的作用。此外，低氧和2-DOG对肠系膜动脉平滑肌细胞的IK(V)和Em影响可忽略不计。这些结果表明，低氧可能通过局部ATP减少触发Kv通道的阻断并使PA肌细胞去极化。这种阻断也可能由细胞氧化还原状态的改变介导，可能是通过与通道蛋白相连的含血红素（或金属）的调节部分的构象变化实现的。
