Pugsley M K, Yu E J, Goldin A L
Department of Microbiology & Molecular Genetics, University of California, Irvine, California, USA.
Exp Clin Cardiol. 2001 Summer;6(2):61-71.
To determine whether the kappa opioid receptor agonist U-50,488H, a benzacetamide derivative of the cyclo-hexane-1,2-diamine analgesics, may be a useful molecular probe to define the structural requirements of this class of drugs for cardiac sodium channel blockade.
The electrophysiological effects of U-50,488H were compared with those of lidocaine, a clinically used class Ib antiarrhythmic agent, in rat heart sodium currents expressed in Xenopus laevis oocytes by using two-electrode voltage clamp.
Both U-50,488H and lidocaine produced a concentration-dependent tonic block of sodium current, but U-50,488H was approximately fourfold more potent than lidocaine. Both drugs produced a hyperpolarizing shift in the voltage dependence of sodium channel inactivation and both delayed recovery from inactivation. Both drugs exhibited use-dependent block, but U-50,488H showed a 1.8-fold increase in potency compared with lidocaine at a high frequency of stimulation (30 Hz).
The more potent tonic and use-dependent block of cardiac sodium channels by U-50,488H suggests that structural features of this molecule may provide it with a greater ability to block the channel. An understanding of these structural features may provide information needed in the development of novel arylacetamide-based antiarrhythmic drugs and insight into possible mechanisms describing channel block, resulting in a highly efficacious antiarrhythmic action in the heart.
确定κ阿片受体激动剂U - 50,488H（一种环己烷 - 1,2 - 二胺镇痛药的苯乙酰胺衍生物）是否可能是一种有用的分子探针，以界定这类药物对心脏钠通道阻滞的结构要求。
通过双电极电压钳技术，在非洲爪蟾卵母细胞中表达的大鼠心脏钠电流上，比较U - 50,488H与临床使用的Ib类抗心律失常药物利多卡因的电生理效应。
U - 50,488H和利多卡因均产生浓度依赖性的钠电流强直阻滞，但U - 50,488H的效力约为利多卡因的四倍。两种药物均使钠通道失活的电压依赖性发生超极化偏移，且均延迟失活后的恢复。两种药物均表现出使用依赖性阻滞，但在高频刺激（30 Hz）下，U - 50,488H的效力比利多卡因高1.8倍。
U - 50,488H对心脏钠通道更有效的强直和使用依赖性阻滞表明，该分子的结构特征可能使其具有更强的通道阻滞能力。了解这些结构特征可能为新型芳基乙酰胺类抗心律失常药物的开发提供所需信息，并深入了解描述通道阻滞的可能机制，从而在心脏中产生高效的抗心律失常作用。
