Pugsley M K, Saint D A, Hayes E S, Kramer D, Walker M J
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
J Cardiovasc Pharmacol. 1998 Dec;32(6):863-74. doi: 10.1097/00005344-199812000-00002.
Spiradoline (U-62,066E), a selective kappa (kappa) receptor agonist, was examined for actions on the cardiovascular system and on myocardial ionic currents in rats. We initially characterized cardiac, hemodynamic, and antiarrhythmic actions of spiradoline in isolated perfused rat hearts and pentobarbital-anesthetized rats. Electrophysiologic studies in isolated myocytes were used to elucidate the mechanism for changes observed in vivo in the ECG, as well as for antiarrhythmic actions against electrical and ischemia-induced arrhythmias. In isolated rat hearts, spiradoline reduced heart rate and cardiac contractility and increased the PR interval and QRS width of the ECG in a concentration-dependent manner. In anesthetized rats, spiradoline dose-dependently reduced blood pressure and heart rate and prolonged the PR interval and QRS width. At slightly higher doses, it increased the QaT interval of the ECG. RSh, an index of sodium channel blockade in the rat, also was dose-dependently increased. Electrical stimulation of the left ventricle suggested that spiradoline may exert its antiarrhythmic action by blockade of myocardial sodium currents. The electrophysiologic actions of spiradoline on sodium currents, the transient outward (i(to)) and sustained plateau potassium (ik(sus)) currents were studied in isolated cardiac rat myocytes by whole-cell patch-clamp techniques. Spiradoline (15-500 microM) reduced peak sodium current in a rapid, reversible, and concentration-dependent manner; it also increased the rate of decay of I(to) and reduced the amplitude of Ik(sus). At a concentration of 150 microM, spiradoline produced a 24 +/- 2 mV hyperpolarizing shift in sodium current inactivation kinetics but did not alter activation processes. Spiradoline showed both tonic and frequency-dependent components of sodium current block. Thus spiradoline produced its antiarrhythmic actions via sodium channel blockade in myocardial tissue, although higher doses also block potassium currents. This combined ion channel-blocking property may be of added clinical benefit in the setting of myocardial ischemia.
螺哌多林（U-62,066E）是一种选择性κ受体激动剂，我们研究了其对大鼠心血管系统和心肌离子电流的作用。我们首先在离体灌注大鼠心脏和戊巴比妥麻醉的大鼠中对螺哌多林的心脏、血流动力学和抗心律失常作用进行了表征。在分离的心肌细胞中进行电生理研究，以阐明体内心电图变化的机制，以及针对电诱导和缺血诱导心律失常的抗心律失常作用。在离体大鼠心脏中，螺哌多林以浓度依赖性方式降低心率和心肌收缩力，并增加心电图的PR间期和QRS宽度。在麻醉大鼠中，螺哌多林剂量依赖性地降低血压和心率，并延长PR间期和QRS宽度。在稍高剂量时，它增加了心电图的QT间期。RSh是大鼠钠通道阻滞的指标，也呈剂量依赖性增加。左心室电刺激表明，螺哌多林可能通过阻断心肌钠电流发挥其抗心律失常作用。通过全细胞膜片钳技术在分离的大鼠心肌细胞中研究了螺哌多林对钠电流、瞬时外向（I(to)）和持续平台钾（Iksus）电流的电生理作用。螺哌多林（15 - 500μM）以快速、可逆和浓度依赖性方式降低峰值钠电流；它还增加了I(to)的衰减速率并降低了Iksus的幅度。在150μM浓度下，螺哌多林使钠电流失活动力学产生24±2mV的超极化偏移，但未改变激活过程。螺哌多林显示出钠电流阻滞的强直和频率依赖性成分。因此，螺哌多林通过阻断心肌组织中的钠通道产生其抗心律失常作用，尽管较高剂量也会阻断钾电流。这种联合的离子通道阻断特性在心肌缺血情况下可能具有额外的临床益处。
