Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase c-δ-mediated mechanism
Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase c-δ-mediated mechanism
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DOI：
10.1097/00000542-200509000-00017
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发表时间：
2005-09-01
期刊：
影响因子：
8.8
通讯作者：
Stadnicka, A
中科院分区：
文献类型：
--
作者：
Marinovic, J;Bosnjak, ZJ;Stadnicka, A
背景资料：在麻醉诱导的预适应中，挥发性麻醉药的心脏保护作用涉及心肌肌膜三磷酸腺苷敏感性钾（sarcK（ATP））通道的激活。本研究通过研究短暂暴露于异氟烷是否会产生sarcK（ATP）通道的持久增敏以及蛋白激酶C是否介导这种效应来解决麻醉预处理的记忆阶段。方法：从单个分离的大鼠心室心肌细胞中监测全细胞sarcK（ATP）通道电流（I-KATP）。吡那地尔用于打开通道，并且激活的I-KATP的幅度是通道打开能力的指标。蛋白激酶C的参与进行了研究，使用白屈菜红碱和亚型特异性肽抑制剂和激活剂的蛋白激酶C-δ和蛋白激酶C-cytokine.Results：平均密度的I-KATP，诱导吡那地尔（5下午）在无麻醉条件下为3.8 +/- 3.7 pA/pF（n = 11）。在暴露于异氟烷（0.56 mm）10 min和麻醉剂洗脱10或30 min后，吡那地尔诱导的I-KATP分别增加至15.6 +/- 11.3 pA/pF（n = 12; P < 0.05）和11.8 +/- 3.9 pA/pF（n = 6; P < 0.05）。在白屈菜红碱（5 μ m）存在下，异氟烷不增强通道开放，I-KATP为6.6 +/- 4.6 pA/pF（n = 11）。蛋白激酶C-δ肽抑制剂的应用也消除了异氟烷诱导的sarcK（ATP）通道的增敏作用，I-KATP为7.7 +/- 5.4 pA/pF（n = 12）。相比之下，蛋白激酶C-E肽抑制剂不影响通道敏化，吡那地尔引起的电流为14.8 +/- 9.6 pA/pF（n = 12）。有趣的是，当蛋白激酶C-δ和蛋白激酶C-δ激活剂代替异氟烷应用时，它们对通道的敏化程度与异氟烷相同（分别为18.9 +/- 7.2 pA/pF，n = 11和18.6 +/- 11.1 pA/pF，n = 10）。异氟烷诱导sarcK（ATP）通道对开放的长期敏感性，即使在麻醉剂戒断后也持续存在。我们的研究结果表明，蛋白激酶C-δ，而不是蛋白激酶C-β，是一个可能的介质异氟烷的影响，虽然蛋白激酶C-δ和蛋白激酶C-β可以调节通道功能。
Background: Cardioprotective effects of volatile anesthetics in anesthetic-induced preconditioning involve activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (sarcK(ATP)) channels. This study addressed the memory phase of anesthetic preconditioning by investigating whether brief exposure to isoflurane produces lasting sensitization of the sarcK(ATP), channel and whether protein kinase C mediates this effect.Methods: Whole cell sarcK(ATP) channel current (I-KATP) was monitored from single isolated rat ventricular cardiomyocytes. Pinacidil was used to open the channel, and the magnitude of activated I-KATP was an indicator of channel's ability to open. Involvement of protein kinase C was investigated using chelerythrine and isoform-specific peptide inhibitors and activators of protein kinase C-delta and protein kinase C-epsilon.Results: The mean density of I-KATP, elicited by pinacidil (5 pm) in anesthetic-free conditions was 3.8 +/- 3.7 pA/pF (n = 11). After 10 min of exposure to isoflurane (0.56 mm) and 10 or 30 min of anesthetic washout, pinacidil-elicited I-KATP was increased to 15.6 +/- 11.3 pA/pF (n = 12; P < 0.05) and 11.8 +/- 3.9 pA/pF (n = 6; P < 0.05), respectively. In the presence of chelerythrine (5 mu m), isoflurane did not potentiate channel opening, and I-KATP was 6.6 +/- 4.6 pA/pF (n = 11). Application of protein kinase C-delta peptide inhibitor also abolished isoflurane-induced sensitization of sarcK(ATP) channel, and I-KATP was 7.7 +/- 5.4 pA/pF (n = 12). In contrast, protein kinase C-E peptide inhibitor did not affect channel sensitization, and pinacidil-elicited current was 14.8 +/- 9.6 pA/pF (n = 12). Interestingly, when both protein kinase C-delta and protein kinase C-epsilon activators were applied instead of isoflurane, they sensitized the channel to the same extent as isoflurane (18.9 +/- 7.2 pA/pF, n = 11, and 18.6 +/- 11.1 pA/pF, n = 10, respectively).Conclusion: Isoflurane induces prolonged sensitization of the sarcK(ATP) channel to opening that persists even after anesthetic withdrawal. Our results indicate that protein kinase C-delta, rather than protein kinase C-epsilon, is a likely mediator of isoflurane effects, although both protein kinase C-delta and protein kinase C-epsilon can modulate the channel function.