KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart.
KN-93, an inhibitor of multifunctional Ca++/calmodulin-dependent protein kinase, decreases early afterdepolarizations in rabbit heart.
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发表时间：
1998-12
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通讯作者：
M. Anderson;A. Braun;Yuejin Wu;T. Lu;H. Schulman;R. Sung
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作者：
M. Anderson;A. Braun;Yuejin Wu;T. Lu;H. Schulman;R. Sung
多功能Ca++/钙调蛋白依赖性蛋白激酶II（CaM激酶）介导Ca++诱导的L型Ca++电流（伊卡）增强;因此，它可能在由伊卡引起的早期后去极化（埃兹）期间作为一种促进性信号分子。为了研究Ca依赖性埃兹受CaM激酶激活的影响这一假设，在离体兔心脏中用氯非铵诱导埃兹。所有埃兹均用伊卡拮抗剂迅速终止。在Clofilium暴露前，用CaM激酶抑制剂KN-93或无活性类似物KN-92（0.5 μ M）预处理心脏10分钟。与KN-92（10/11心脏中存在EAD）相比，KN-93（4/10心脏中存在EAD）显著抑制埃兹（P =.024）。在KN-93或KN-92处理的心脏中，有利于埃兹的参数（如单相动作电位时程或心率）无显著差异。与无埃兹的心脏相比，EADs心脏的CaM激酶原位活性增加了37%（P = 0.015）。这种CaM激酶活性的增加被KN-93预处理所阻止。在体外，KN-93有效抑制兔心肌CaM激酶活性（计算Ki 100 microM）。KN-93和KN-92对伊卡和其他复极化K+电流的作用不能解释KN-93对EAD的优先抑制。这些数据显示了钙调素激酶激活和埃兹之间的一种新的关联，并与该模型中伊卡和钙调素激酶激活均有助于埃兹的假设一致。
The multifunctional Ca++/calmodulin-dependent protein kinase II (CaM kinase) mediates Ca++-induced augmentation of L-type Ca++ current (ICa); therefore it may act as a proarrhythmic signaling molecule during early afterdepolarizations (EADs) due to ICa. To investigate the hypothesis that ICa-dependent EADs are favored by CaM kinase activation EADs were induced with clofilium in isolated rabbit hearts. All EADs were rapidly terminated with ICa antagonists. Hearts were pretreated with the CaM kinase inhibitor KN-93 or the inactive analog KN-92 (0.5 microM) for 10 min before clofilium exposure. EADs were significantly suppressed by KN-93 (EADs present in 4/10 hearts) compared to KN-92 (EADs present in 10/11 hearts) (P =.024). There were no significant differences in parameters favoring EADs such as monophasic action potential duration or heart rate in KN-93- or KN-92-treated hearts. CaM kinase activity in situ increased 37% in hearts with EADs compared to hearts without EADs (P =.015). This increase in CaM kinase activity was prevented by pretreatment with KN-93. In vitro, KN-93 potently inhibited rabbit myocardial CaM kinase activity (calculated Ki 100 microM). The actions of KN-93 and KN-92 on ICa and other repolarizing K+ currents did not explain preferential EAD suppression by KN-93. These data show a novel association between CaM kinase activation and EADs and are consistent with the hypothesis that the ICa and CaM kinase activation both contribute to EADs in this model.