Suzuki Akihiro, Bosnjak Zeljko J, Kwok Wai-Meng
Departments of *Anesthesiology, †Physiology, and ‡Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Anesth Analg. 2003 May;96(5):1308-1315. doi: 10.1213/01.ANE.0000057604.56578.77.
The slowly activating delayed-rectifier potassium current, IKs, is a major outward current responsible for the repolarization of the cardiac action potential (AP). Dysfunction of this channel can lead to AP prolongation, resulting in the long QT syndrome. We hypothesized that anesthetic-induced AP prolongation is caused by inhibition of IKs, in addition to the inhibition of IKr (rapidly activating delayed-rectifier potassium channel current), a condition often found in drug-induced AP prolongation. The whole-cell patch clamp technique was used to study the effects of isoflurane on IKs and IKr recorded from guinea pig single ventricular myocytes. The effect of protein kinase C on IKs inhibition by isoflurane was also investigated. Isoflurane inhibited IKs in a concentration- and temperature-dependent manner. The inhibitory effects of isoflurane at clinically relevant concentrations of 0.3 and 0.6 mM were greater at 22 degrees C than at 36 degrees C. Voltage-dependent activation of IKs was not affected at these concentrations. IKs deactivation kinetics were accelerated by isoflurane at 22 degrees C but not at 36 degrees C. Isoflurane inhibition of IKs was significantly greater than that of IKr. Protein kinase C activation enhanced IKs but did not suppress the inhibitory effect of isoflurane. Our results suggest that IKs inhibition is one of the mechanisms underlying anesthetic-induced AP and QT prolongation. Because most of the ion channel studies on anesthetic effects are conducted at room temperature, the temperature-dependent effect on IKs confirms the importance of anesthetic experiments conducted at physiological temperature.
The effects of a volatile anesthetic, isoflurane, were determined on a cardiac potassium channel current, IKs, a major ionic component underlying the cardiac action potential. The result shows that IKs is significantly inhibited by isoflurane. This may contribute to anesthetic-induced changes in the electrocardiogram, particularly the prolongation of the QT interval.
缓慢激活延迟整流钾电流（IKs）是负责心脏动作电位（AP）复极化的主要外向电流。该通道功能障碍可导致AP延长，进而引发长QT综合征。我们推测，除了抑制快速激活延迟整流钾通道电流（IKr）（药物诱导的AP延长中常见的一种情况）外，麻醉诱导的AP延长是由IKs抑制引起的。采用全细胞膜片钳技术研究异氟烷对豚鼠单个心室肌细胞记录的IKs和IKr的影响。还研究了蛋白激酶C对异氟烷抑制IKs的作用。异氟烷以浓度和温度依赖性方式抑制IKs。在临床相关浓度0.3和0.6 mM时，异氟烷在22℃时的抑制作用大于在36℃时。在这些浓度下，IKs的电压依赖性激活不受影响。在22℃时，异氟烷加速IKs失活动力学，但在36℃时则不然。异氟烷对IKs的抑制作用明显大于对IKr的抑制作用。蛋白激酶C激活增强IKs，但不抑制异氟烷的抑制作用。我们的结果表明，IKs抑制是麻醉诱导的AP和QT延长的潜在机制之一。由于大多数关于麻醉作用的离子通道研究是在室温下进行的，对IKs的温度依赖性影响证实了在生理温度下进行麻醉实验的重要性。
确定了挥发性麻醉剂异氟烷对心脏钾通道电流IKs的影响，IKs是心脏动作电位的主要离子成分。结果表明，异氟烷显著抑制IKs。这可能导致麻醉引起的心电图变化，特别是QT间期延长。
