Kang Jiesheng, Reynolds William P, Chen Xiao-Liang, Ji Junzhi, Wang Hongge, Rampe David E
Department of Drug Safety Evaluation, Sanofi-Aventis U.S. Inc., Bridgewater, New Jersey 08807-0800, USA.
Anesthesiology. 2006 May;104(5):1015-22. doi: 10.1097/00000542-200605000-00018.
Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed.
The effects of sevoflurane on action potentials and L-type Ca channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K channels and the cloned human cardiac Na channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined.
Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K channel currents and inhibited the Kv4.3 K channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na and Ca channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%).
Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.
七氟醚可延长患者的心室复极化时间，但其机制尚未完全明确。七氟醚对多种克隆的人类心脏离子通道的影响尚未得到研究，并且七氟醚与其他延长心脏复极化时间的药物之间的相互作用也未详细阐明。
研究了七氟醚对豚鼠心肌细胞动作电位和L型钙通道的影响。研究了七氟醚对克隆的人类心脏钾通道和克隆的人类心脏钠通道的作用。还研究了七氟醚与Ⅲ类抗心律失常药物索他洛尔或多非利特联合使用对动作电位时程的影响。
七氟醚在浓度为0.3 - 1 mM时可使动作电位时程延长。与大多数延迟心室复极化的药物相反，七氟醚对人类醚 - 去极化相关基因心脏钾通道没有影响，反而使KvLQT1/minK钾通道电流降低，并通过加快其明显的失活速率来抑制Kv4.3钾通道。七氟醚在浓度为1 mM或更低时对钠通道和钙通道电流影响很小。当作者将七氟醚与索他洛尔或多非利特联合给药时，观察到对复极化有协同作用，导致动作电位时程大幅增加（高达66%）。
七氟醚给药后观察到的心室复极化延长是由于抑制了KvLQT1/minK和Kv4.3心脏钾通道。七氟醚与Ⅲ类抗心律失常药物联合使用会对动作电位时程产生超相加效应。结果表明，七氟醚与这类药物联合使用时，可能会导致心室复极化过度延迟。结果提示需要进一步进行临床研究。
