Krafte D S, Volberg W A
Sterling Winthrop, Inc., Collegeville, PA 19426-0900.
J Cardiovasc Pharmacol. 1994 Jan;23(1):37-41. doi: 10.1097/00005344-199401000-00005.
Voltage-clamp experiments were performed on isolated guinea pig ventricular myocytes to examine the voltage dependence of delayed rectifier block by methanesulfonamide channel blockers. Voltage-dependent channel block, in which block decreases as membrane potential is made more positive, could contribute to the phenomenon of reverse use dependence, in which the magnitude of the drug-induced prolongation in action potential duration (APD) is inversely proportional to stimulation rate. To determine whether such a voltage dependence exists, concentration-response curves were generated for dofetilide, E-4031, sematilide, and D,L-sotalol at test potentials ranging from 0 to 60 mV. All agents blocked current in a manner consistent with selective blockade of the rapidly activating component of delayed rectifier current, IKr. The rank order of potency was E-4031 approximately dofetilide > sematilide > sotalol. Block of tail currents by this class of compounds was more potent after test potentials to +60 mV than after those < or = 0-10 mV. These data are inconsistent with voltage-dependent channel block being a contributing factor to reverse use-dependence and suggest that other mechanisms must be responsible for this phenomenon.
对分离的豚鼠心室肌细胞进行电压钳实验，以研究甲磺酰胺通道阻滞剂对延迟整流器阻滞的电压依赖性。电压依赖性通道阻滞，即随着膜电位更正，阻滞作用减弱，可能导致反向使用依赖性现象，即药物诱导的动作电位时程（APD）延长幅度与刺激频率成反比。为了确定是否存在这种电压依赖性，在0至60 mV的测试电位下，生成了多非利特、E-4031、司美利特和D,L-索他洛尔的浓度-反应曲线。所有药物均以与选择性阻滞延迟整流电流IKr的快速激活成分一致的方式阻断电流。效价顺序为E-4031≈多非利特＞司美利特＞索他洛尔。与测试电位＜或=0-10 mV相比，这类化合物在测试电位至+60 mV后对尾电流的阻断作用更强。这些数据与电压依赖性通道阻滞是反向使用依赖性的一个促成因素不一致，表明其他机制必定是导致此现象的原因。
