Effects of intracellular MgADP and acidification on the inhibition of cardiac sarcolemmal ATP-sensitive potassium channels by propofol
Effects of intracellular MgADP and acidification on the inhibition of cardiac sarcolemmal ATP-sensitive potassium channels by propofol
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DOI：
10.1007/s00540-007-0551-9
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发表时间：
2007-11
影响因子：
2.8
通讯作者：
Hirohide Yamada;T. Kawano;Katsuya Tanaka;Sonoko Yasui;K. Mawatari;A. Takahashi;Y. Nakaya;S. Oshita
中科院分区：
文献类型：
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作者：
Hirohide Yamada;T. Kawano;Katsuya Tanaka;Sonoko Yasui;K. Mawatari;A. Takahashi;Y. Nakaya;S. Oshita
目的异丙酚抑制三磷酸腺苷敏感钾 (KATP) 通道，可能导致心脏缺血预适应的阻断。在心脏缺血期间，肌膜 KATP 通道活性受到胞质代谢物（如二磷酸腺苷 (ADP) 和质子）水平增加的调节。然而，尚不清楚这些胞质代谢物是否调节异丙酚的抑制作用。本研究的目的是探讨细胞内 MgADP 和酸化对异丙酚 KATP 通道抑制的影响。方法我们使用内向外膜片钳配置来研究异丙酚对重组心脏肌膜 KATP 通道活性的影响，该通道由表达亚基磺酰脲受体 (SUR) 2A 和内向整流钾通道 (Kir6.2) 重新关联。 MgADP、异丙酚以浓度依赖性方式抑制SUR2A/Kir6.2通道电流，IC50为78μM。将细胞内 MgADP 浓度增加至 0.1 和 0.3mM 会显着减弱丙泊酚的抑制效力，并使 IC50 分别变为 183 和 265μM。此外，将细胞内 pH 从 7.4 降低至 6.5 会减弱异丙酚的抑制效力，并将 IC50 变为 277μM。此外，异丙酚诱导的截短的 Kir6.2ΔC36 电流（形成一个没有 SUR2A 的功能通道）的抑制不受细胞内 MgADP 增加的影响。然而，细胞内酸化（pH 6.5）显着降低了Kir6.2ΔC36通道的异丙酚敏感性。结论我们的结果表明，细胞内MgADP和质子的存在分别通过SUR2A和Kir6.2亚基减弱了异丙酚对重组心脏肌膜KATP通道的直接抑制效力。
PurposePropofol inhibits adenosine triphosphate-sensitive potassium (KATP) channels, which may result in the blocking of ischemic preconditioning in the heart. During cardiac ischemia, sarcolemmal KATPchannel activity is regulated by the increased levels of cytosolic metabolites, such as adenosine diphosphate (ADP) and protons. However, it remains unclear whether these cytosolic metabolites modulate the inhibitory action of propofol. The aim of this study was to investigate the effects of intracellular MgADP and acidification on KATPchannel inhibition by propofol.MethodsWe used inside-out patch-clamp configurations to investigate the effects of propofol on the activities of recombinant cardiac sarcolemmal KATPchannels, which are reassociated by expressed subunits, sulfonylurea receptor (SUR) 2A, and inwardly rectifying potassium channels (Kir6.2).ResultsIn the absence of MgADP, propofol inhibited the SUR2A/Kir6.2 channel currents in a concentration-dependent manner, and an IC50of 78 µM. Increasing the intracellular MgADP concentrations to 0.1 and 0.3 mM markedly attenuated the inhibitory potency of propofol, and shifted the IC50to 183 and 265 µM, respectively. Moreover, decreasing the intracellular pH from 7.4 to 6.5 attenuated the inhibitory potency of propofol, and shifted the IC50to 277 µM. In addition, propofol-induced inhibition of truncated Kir6.2ΔC36 currents, which form a functional channel without SUR2A, was not affected by an increase in intracellular MgADP. However, intracellular acidification (pH 6.5) significantly reduced the propofol sensitivity of Kir6.2ΔC36 channels.ConclusionOur results demonstrated that the existence of intracellular MgADP and protons attenuated the direct inhibitory potency of propofol on recombinant cardiac sarcolemmal KATPchannels, via SUR2A and Kir6.2 subunits, respectively.