Nakamura Akiyo, Kawahito Shinji, Kawano Takashi, Nazari Hossein, Takahashi Akira, Kitahata Hiroshi, Nakaya Yutaka, Oshita Shuzo
Department of Anesthesiology, University of Tokushima Graduate School, Tokushima, Japan.
Anesthesiology. 2007 Mar;106(3):515-22. doi: 10.1097/00000542-200703000-00016.
The aim of this study was to investigate the effects of two imidazoline-derived intravenous anesthetics, etomidate and midazolam, on vascular adenosine triphosphate-sensitive potassium (KATP) channel activity.
In isolated rat aorta, isometric tension was recorded to examine the anesthetic effects on vasodilator response to levcromakalim, a selective KATP channel opener. Using the patch clamp method, the anesthetic effects were also examined on the currents through (1) native vascular KATP channels, (2) recombinant KATP channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits, (3) SUR-deficient channels derived from a truncated isoform of Kir6.2 subunit (Kir6.2DeltaC36 channels), and (4) mutant Kir6.2DeltaC36 channels with reduced sensitivity to adenosine triphosphate (Kir6.2DeltaC36-K185Q channels).
Etomidate (> or = 10 m), but not midazolam (up to 10 m), inhibited the levcromakalim-induced vasodilation, which was sensitive to glibenclamide (IC50: 7.21 x 10 m; maximum inhibitory concentration: 1.22 x 10 m). Etomidate (> or = 3 x 10 m), but not midazolam (up to 10 m), inhibited the native KATP channel activity in both cell-attached and inside-out configurations with IC50 values of 1.68 x 10 m and 1.52 x 10 m, respectively. Etomidate (10 m) also inhibited the activity of various types of recombinant SUR/Kir6.0KATP channels, Kir6.2DeltaC36 channels, and Kir6.2DeltaC36-K185Q channels with equivalent potency.
Clinical concentrations of etomidate, but not midazolam, inhibit the KATP channel activity in vascular smooth muscle cells. The inhibition is presumably through its effects on the Kir6.0 subunit, but not on the SUR subunit, with the binding site different from adenosine triphosphate at the amino acid level.
本研究旨在探讨两种咪唑啉类静脉麻醉药依托咪酯和咪达唑仑对血管三磷酸腺苷敏感性钾（KATP）通道活性的影响。
在离体大鼠主动脉中，记录等长张力以检测麻醉药对选择性KATP通道开放剂左卡尼汀诱导的血管舒张反应的影响。采用膜片钳技术，还检测了麻醉药对以下电流的影响：（1）天然血管KATP通道；（2）由不同组合的内向整流钾通道（Kir6.0家族：Kir6.1、6.2）和磺脲类受体（SUR1、2A、2B）亚基组成的重组KATP通道；（3）源自Kir6.2亚基截短异构体的SUR缺陷通道（Kir6.2DeltaC36通道）；（4）对三磷酸腺苷敏感性降低的突变型Kir6.2DeltaC36通道（Kir6.2DeltaC36-K185Q通道）。
依托咪酯（≥10 μmol/L）而非咪达唑仑（高达10 μmol/L）可抑制左卡尼汀诱导的血管舒张，该抑制作用对格列本脲敏感（IC50：7.21×10 μmol/L；最大抑制浓度：1.22×10 μmol/L）。依托咪酯（≥3×10 μmol/L）而非咪达唑仑（高达10 μmol/L）可抑制细胞贴附式和外向式两种模式下的天然KATP通道活性，IC50值分别为1.68×10 μmol/L和1.52×10 μmol/L。依托咪酯（10 μmol/L）还能同等程度地抑制各种类型的重组SUR/Kir6.0 KATP通道、Kir6.2DeltaC36通道和Kir6.2DeltaC36-K185Q通道的活性。
临床浓度的依托咪酯而非咪达唑仑可抑制血管平滑肌细胞中的KATP通道活性。这种抑制作用可能是通过其对Kir6.0亚基而非SUR亚基的作用实现的，其结合位点在氨基酸水平上与三磷酸腺苷不同。
