Wettwer E, Grundke M, Ravens U
Pharmakologisches Institut, Universität-Gesamthochschule-Essen, Germany.
Cardiovasc Res. 1992 Nov;26(11):1145-52. doi: 10.1093/cvr/26.11.1145.
The effects of almokalant (4-[3-ethyl[3-(propylsulphinyl)propyl]-amino]-2-hydroxy-propoxy]- benzonitrile), E-4031 (1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulphonyl-amino- benzoyl)piperidine), d-sotalol, and quinidine were investigated on the delayed K+ rectifier current IK. The aim of the study was to compare the drug action on the two components of this current.
Membrane currents were measured in ventricular myocytes from guinea pig hearts with the whole cell voltage clamp technique. IK was activated during clamp steps from a holding potential of -40 mV to test potentials -30 and +50 mV. The tail current Itail was measured upon stepping back to holding potential.
In control experiments. IK and Itail declined spontaneously ("run down"). With 300 ms long test pulses to +50 mV, only d-sotalol (10(-4) M) caused a significant further decrease in IK, whereas all four agents significantly reduced Itail (almokalant 10(-6) M, E-4031 10(-7) M, quinidine 10(-5) M). When tested with 1 s long clamp steps at various potentials almokalant (3 x 10(-6) M), E-4031 (10(-6) M), quinidine (10(-5) M), and d-sotalol (10(-4) M) reduced IK in the potential range between -20 and +40 mV, yielding a bell shaped inward rectifying drug sensitive current. Itail was reduced by almokalant and E-4031 over the whole voltage range with saturation of block positive to +20 mV. Similar reductions with quinidine but not with d-sotalol were also significant. With rest pulses to +50 mV of increasing duration (25 ms-4000 ms), Itail developed with a faster time course than IK and therefore the ratio of Itail/IK declined with pulse duration. With almokalant and E-4031, this ratio became independent of test pulse duration. For 250 ms pulses, Itail/IK was also significantly reduced by d-sotalol and quinidine.
Inhibition of the rapidly activating inwardly rectifying component of IK is prominent with almokalant and E-4031 and less pronounced with d-sotalol and quinidine. Since inhibition of this component prolongs the cardiac action potential, it should contribute to the antiarrhythmic properties of the agents.
研究了阿尔莫卡兰特（4-[3-乙基[3-(丙基亚磺酰基)丙基]-氨基]-2-羟基-丙氧基]-苯甲腈）、E-4031（1-[2-(6-甲基-2-吡啶基)-乙基]-4-(4-甲磺酰基-氨基-苯甲酰基)哌啶）、d-索他洛尔和奎尼丁对延迟钾离子整流电流IK的影响。本研究的目的是比较这些药物对该电流两个成分的作用。
采用全细胞电压钳技术测量豚鼠心室肌细胞的膜电流。在从-40 mV的钳制电位到测试电位-30 mV和+50 mV的钳制步骤中激活IK。在回到钳制电位时测量尾电流Itail。
在对照实验中，IK和Itail自发下降（“衰减”）。用300 ms长的测试脉冲至+50 mV时，只有d-索他洛尔（10(-4) M）导致IK进一步显著下降，而所有四种药物均显著降低Itail（阿尔莫卡兰特10(-6) M、E-4031 10(-7) M、奎尼丁10(-5) M）。当在不同电位下用1 s长的钳制步骤进行测试时，阿尔莫卡兰特（3×10(-6) M）、E-4031（10(-6) M）、奎尼丁（10(-5) M）和d-索他洛尔（10(-4) M）在-20至+40 mV的电位范围内降低IK，产生钟形内向整流药物敏感电流。阿尔莫卡兰特和E-4031在整个电压范围内降低Itail，在正向至+20 mV时阻断达到饱和。奎尼丁也有类似的降低，但d-索他洛尔则没有，且差异显著。随着对+50 mV的静息脉冲持续时间增加（25 ms - 4000 ms），Itail的变化时程比IK更快，因此Itail/IK的比值随脉冲持续时间下降。使用阿尔莫卡兰特和E-4031时，该比值与测试脉冲持续时间无关。对于250 ms的脉冲，d-索他洛尔和奎尼丁也显著降低了Itail/IK。
阿尔莫卡兰特和E-4031对IK快速激活的内向整流成分的抑制作用显著，而d-索他洛尔和奎尼丁的作用较弱。由于对该成分的抑制会延长心脏动作电位，因此这应有助于这些药物的抗心律失常特性。
