Stadnicka Anna, Bosnjak Zeljko J
Department of Anesthesiology, the Medical College of Wisconsin, Milwaukee 53226, USA.
Anesthesiology. 2003 Feb;98(2):396-403. doi: 10.1097/00000542-200302000-00020.
Volatile anesthetics can protect the myocardium against ischemic injury by opening the adenosine triphosphate (ATP)-sensitive potassium (K(atp)) channels. However, direct evidence for anesthetic-channel interaction is still limited, and little is known about the role K(atp) channel modulators play in this effect. Because pH is one of the regulators of K(atp) channels, the authors tested the hypothesis that intracellular pH (pHi) modulates the direct interaction of isoflurane with the cardiac K(atp) channel.
The effects of isoflurane on sarcolemmal K(atp) channels were investigated at pHi 7.4 and pHi 6.8 in excised inside-out membrane patches from ventricular myocytes of guinea pig hearts.
At pHi 7.4, intracellular ATP (1-1,000 microm) inhibited K(atp) channels and decreased channel open probability (Po) in a concentration-dependent manner with an IC(50) of 8 +/- 1.5 microm, and isoflurane (0.5 mm) either had no effect or decreased channel activity. Lowering pHi from 7.4 to 6.8 enhanced channel opening by increasing Po and reduced channel sensitivity to ATP, with IC shifting from 8 +/- 1.2 to 45 +/- 5.6 microm. When applied to the channels activated at pHi 6.8, isoflurane (0.5 mm) increased Po and further reduced ATP sensitivity, shifting IC(50) to 110 +/- 10.0 microm.
Changes in pHi appear to modulate isoflurane interaction with the cardiac K(atp) channel. At pHi 6.8, which itself facilitates channel opening, isoflurane enhances channel activity by increasing Po and reduces sensitivity to inhibition by ATP without changing the unitary amplitude of single channel current or the conductance. These results support the hypothesis of direct isoflurane-K(atp) channel interaction that may play a role in cardioprotection by volatile anesthetics.
挥发性麻醉药可通过开放三磷酸腺苷（ATP）敏感性钾（K（atp））通道来保护心肌免受缺血性损伤。然而，麻醉药与通道相互作用的直接证据仍然有限，关于K（atp）通道调节剂在这种效应中所起的作用知之甚少。由于pH是K（atp）通道的调节因子之一，作者检验了细胞内pH（pHi）调节异氟烷与心脏K（atp）通道直接相互作用的假设。
在豚鼠心脏心室肌细胞的内向外膜片上，于pHi 7.4和pHi 6.8条件下研究异氟烷对肌膜K（atp）通道的影响。
在pHi 7.4时，细胞内ATP（1 - 1000微摩尔）以浓度依赖性方式抑制K（atp）通道并降低通道开放概率（Po），半数抑制浓度（IC（50））为8±1.5微摩尔，而异氟烷（0.5毫摩尔）要么无作用，要么降低通道活性。将pHi从7.4降至6.8可通过增加Po来增强通道开放，并降低通道对ATP的敏感性，IC（50）从8±1.2微摩尔变为45±5.6微摩尔。当应用于在pHi 6.8时被激活的通道时，异氟烷（0.5毫摩尔）增加Po并进一步降低ATP敏感性，使IC（50）变为110±10.0微摩尔。
pHi的变化似乎可调节异氟烷与心脏K（atp）通道的相互作用。在pHi 6.8时，其本身有利于通道开放，异氟烷通过增加Po来增强通道活性，并降低对ATP抑制的敏感性，而不改变单通道电流的单位幅度或电导率。这些结果支持异氟烷与K（atp）通道直接相互作用的假设，这可能在挥发性麻醉药的心脏保护作用中发挥作用。
