Kawano Takashi, Oshita Shuzo, Takahashi Akira, Tsutsumi Yasuo, Tanaka Katsuya, Tomiyama Yoshinobu, Kitahata Hiroshi, Nakaya Yutaka
Department of Anesthesiology, Tokushima University School of Medicine, Tokushima, Japan.
Anesthesiology. 2005 Jan;102(1):93-101. doi: 10.1097/00000542-200501000-00017.
Ketamine inhibits adenosine triphosphate-sensitive potassium (KATP) channels, which results in the blocking of ischemic preconditioning in the heart and inhibition of vasorelaxation induced by KATP channel openers. In the current study, the authors investigated the molecular mechanisms of ketamine's actions on sarcolemmal KATP channels that are reassociated by expressed subunits, inwardly rectifying potassium channels (Kir6.1 or Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, or SUR2B).
The authors used inside-out patch clamp configurations to investigate the effects of ketamine on the activities of reassociated Kir6.0/SUR channels containing wild-type, mutant, or chimeric SURs expressed in COS-7 cells.
Ketamine racemate inhibited the activities of the reassociated KATP channels in a SUR subtype-dependent manner: SUR2A/Kir6.2 (IC50 = 83 microM), SUR2B/Kir6.1 (IC50 = 77 microM), SUR2B/Kir6.2 (IC50 = 89 microM), and SUR1/Kir6.2 (IC50 = 1487 microM). S-(+)-ketamine was significantly less potent than ketamine racemate in blocking all types of reassociated KATP channels. The ketamine racemate and S-(+)-ketamine both inhibited channel currents of the truncated isoform of Kir6.2 (Kir6.2DeltaC36) with very low affinity. Application of 100 mum magnesium adenosine diphosphate significantly enhanced the inhibitory potency of ketamine racemate. The last transmembrane domain of SUR2 was essential for the full inhibitory effect of ketamine racemate.
These results suggest that ketamine-induced inhibition of sarcolemmal KATP channels is mediated by the SUR subunit. These inhibitory effects of ketamine exhibit specificity for cardiovascular KATP channels, at least some degree of stereoselectivity, and interaction with intracellular magnesium adenosine diphosphate.
氯胺酮抑制三磷酸腺苷敏感性钾（KATP）通道，这会导致心脏缺血预处理被阻断以及KATP通道开放剂诱导的血管舒张受到抑制。在本研究中，作者探究了氯胺酮对由表达的亚基、内向整流钾通道（Kir6.1或Kir6.2）和磺脲类受体（SUR1、SUR2A或SUR2B）重新组装的肌膜KATP通道的作用分子机制。
作者采用内面向外膜片钳配置，以研究氯胺酮对在COS-7细胞中表达的包含野生型、突变型或嵌合型SUR的重新组装的Kir6.0/SUR通道活性的影响。
消旋氯胺酮以SUR亚型依赖性方式抑制重新组装的KATP通道活性：SUR2A/Kir6.2（半数抑制浓度[IC50]=83微摩尔）、SUR2B/Kir6.1（IC50=77微摩尔）、SUR2B/Kir6.2（IC50=89微摩尔）和SUR1/Kir6.2（IC50=1487微摩尔）。S-(+)-氯胺酮在阻断所有类型的重新组装的KATP通道方面，效力明显低于消旋氯胺酮。消旋氯胺酮和S-(+)-氯胺酮均以非常低的亲和力抑制Kir6.2截短异构体（Kir6.2DeltaC36）的通道电流。应用100微摩尔的镁二磷酸腺苷可显著增强消旋氯胺酮的抑制效力。SUR2的最后一个跨膜结构域对于消旋氯胺酮的完全抑制作用至关重要。
这些结果表明，氯胺酮诱导的肌膜KATP通道抑制是由SUR亚基介导的。氯胺酮的这些抑制作用对心血管KATP通道具有特异性，至少具有一定程度的立体选择性，并与细胞内镁二磷酸腺苷相互作用。
