Karle Christoph A, Bauer Alexander, Weretka Slawomir, Zitron Edgar, Abushi Adel, Kreye Volker A W, Schoels Wolfgang
3rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Germany.
Basic Res Cardiol. 2002 Jan;97(1):17-25. doi: 10.1007/s395-002-8383-9.
Chromanol 293B and dofetilide are inhibitors of IKs and IKr, i.e., of the slow and the rapid component of the delayed rectifier potassium current. The specificity of these drugs was tested by investigating their effects on the delayed rectifier potassium current in vascular smooth muscle, regulating the tone of blood vessels. Using depolarizing step protocols with asymmetrical potassium concentrations (135/4.5 mM K+ in pipette/bath), voltage-dependent K+ currents (IKv) of enzymatically dispersed guinea pig portal vein cells were studied in the whole-cell patch-clamp technique. Peak currents were obtained within 20 ms (at +50 mV) after activation. During a 10 s test pulse to +60 mV, these currents exhibited a relatively fast inactivation with time constants of 384 ms (Tfast) and 4505 ms (Tslow). Dofetilide was totally ineffective in modulating currents; in contrast, after application of chromanol 293B, a steady-state block of IKv developed within 135 s. The block was concentration-dependent with an IC50 of 7.4 microM. Chromanol did not produce any shift in the normalized steady-state activation and inactivation curves and the recovery from inactivation was not significantly changed. Chromanol 293B similarly inhibited delayed rectifier K+ channels whether in their closed or open state, and produced an "apparent" acceleration of inactivation, i.e., the drug accelerated the faster time constant of inactivation during a 10 s test pulse from 384 ms (control) to 149 ms (100 microM chromanol). In recent studies, chromanol was described as a specific blocker of slowly activating delayed rectifier potassium channels (IKs) in cardiomyocytes. The results of this study, however, extend the inhibitory spectrum of the drug and demonstrate block of closed and open state delayed rectifier K+ currents in portal vein vascular smooth muscle. Such a block could possibly contribute to the generation of portal hypertension.
色满醇293B和多非利特是IKs和IKr的抑制剂，即延迟整流钾电流的慢速和快速成分的抑制剂。通过研究这些药物对血管平滑肌中延迟整流钾电流的影响来测试其特异性，血管平滑肌可调节血管张力。使用具有不对称钾浓度（移液管/浴槽中为135/4.5 mM K+）的去极化阶跃方案，采用全细胞膜片钳技术研究酶分散的豚鼠门静脉细胞的电压依赖性钾电流（IKv）。激活后20毫秒内（在+50 mV时）获得峰值电流。在向+60 mV的10秒测试脉冲期间，这些电流表现出相对快速的失活，时间常数分别为384毫秒（Tfast）和4505毫秒（Tslow）。多非利特在调节电流方面完全无效；相反，应用色满醇293B后，在135秒内IKv出现稳态阻断。该阻断呈浓度依赖性，IC50为7.4 microM。色满醇在归一化稳态激活和失活曲线中未产生任何偏移，失活恢复也未显著改变。色满醇293B同样抑制延迟整流钾通道，无论其处于关闭还是开放状态，并产生“明显”的失活加速，即该药物在10秒测试脉冲期间将更快的失活时间常数从384毫秒（对照）加速至149毫秒（100 microM色满醇）。在最近的研究中，色满醇被描述为心肌细胞中缓慢激活的延迟整流钾通道（IKs）的特异性阻滞剂。然而，本研究结果扩展了该药物的抑制谱，并证明其可阻断门静脉血管平滑肌中关闭和开放状态的延迟整流钾电流。这种阻断可能有助于门静脉高压的产生。
