Tricarico D, Pierno S, Mallamaci R, Brigiani G S, Capriulo R, Santoro G, Camerino D C
Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, 70126 Bari, Italy.
Mol Pharmacol. 1998 Jul;54(1):197-206. doi: 10.1124/mol.54.1.197.
We evaluated the involvement of the sarcolemmal ATP-sensitive K+ channel in the depolarization of skeletal muscle fibers occurring in an animal model of human hypokalemic periodic paralysis, the K+-depleted rat. After 23-36 days of treatment with a K+-free diet, an hypokalemia was observed in the rats. No difference in the fasting insulinemia and glycemia was found between normokalemic and hypokalemic rats. The fibers of the hypokalemic rats were depolarized. In these fibers, the current of sarcolemmal ATP-sensitive K+ channels measured by the patch-clamp technique was abnormally reduced. Cromakalim, a K+ channel opener, enhanced the current and repolarized the fibers. At channel level, two open conductance states blocked by ATP and stimulated by cromakalim were found in the hypokalemic rats. The two states could be distinguished on the basis of their slope conductance and open probability and were never detected on muscle fibers of normokalemic rats. It is known that insulin in humans affected by hypokalemic periodic paralysis leads to fiber depolarization and provokes paralysis. We therefore examined the effects of insulin at macroscopic and single-channel level on hypokalemic rats. In normokalemic animals, insulin applied in vitro to the muscles induced a glybenclamide-sensitive hyperpolarization of the fibers and also stimulated the sarcolemmal ATP-sensitive K+ channels. In contrast, in hypokalemic rats, insulin caused a pronounced fiber depolarization and reduced the residual currents. Our data indicated that in hypokalemic rats, an abnormally low activity of ATP-sensitive K+ channel is responsible for the fiber depolarization that is aggravated by insulin.
我们评估了肌膜ATP敏感性钾通道在人类低钾性周期性麻痹动物模型——低钾大鼠中发生的骨骼肌纤维去极化过程中的作用。在用无钾饮食治疗23 - 36天后，观察到大鼠出现低钾血症。正常血钾和低钾血症大鼠的空腹胰岛素血症和血糖水平没有差异。低钾血症大鼠的纤维发生了去极化。在这些纤维中，通过膜片钳技术测量的肌膜ATP敏感性钾通道电流异常降低。钾通道开放剂克罗卡林增强了电流并使纤维复极化。在通道水平上，在低钾血症大鼠中发现了两种被ATP阻断并受克罗卡林刺激的开放电导状态。这两种状态可以根据它们的斜率电导和开放概率来区分，而在正常血钾大鼠的肌肉纤维中从未检测到。已知受低钾性周期性麻痹影响的人类体内胰岛素会导致纤维去极化并引发麻痹。因此，我们在宏观和单通道水平上研究了胰岛素对低钾血症大鼠的影响。在正常血钾动物中，体外应用于肌肉的胰岛素诱导纤维出现格列本脲敏感的超极化，并且还刺激了肌膜ATP敏感性钾通道。相反，在低钾血症大鼠中，胰岛素导致明显的纤维去极化并降低了残余电流。我们的数据表明，在低钾血症大鼠中，ATP敏感性钾通道活性异常低下是纤维去极化的原因，而胰岛素会加剧这种去极化。
