Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1+minK channels
Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1+minK channels
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DOI：
10.1038/sj.bjp.0706302
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发表时间：
2005-09-01
影响因子：
7.3
通讯作者：
Delpón, E
中科院分区：
文献类型：
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作者：
Gómez, R;Núñez, L;Delpón, E
1螺内酯（SP）及其主要代谢产物坎利酸（CA）均能延长心肌动作电位时程，降低Kv11.1（HERG）电流。我们检测了SP和CA对心脏hKv1.5、Kv4.3和Kv7.1+minK通道的影响，这些通道产生人I-Kur、I-to 1和I-Ks，2在稳定转染的小鼠成纤维细胞中记录hKv1.5电流，在瞬时转染的中国仓鼠卵巢细胞中记录Kv4.3和Kv7.1 + minK电流。细胞膜片钳。3 SP（1 μ M）和CA（1 nM）分别抑制hKv1.5电流23.2 +/- 3.2和18.9 +/-2.7%，将激活曲线的中点移到更负的电位，并延迟尾部失活的时间过程。4 SP（1 μ M）和CA（1 nM）在+50 mV时，通过Kv4.3通道的总电荷分别抑制27.1 +/-6.4和27.4 +/-5.7%，并加速电流衰减的时间过程。CA而不是SP使失活曲线向更高的超极化电位移动（V-h-37.0 +/- 1.8 vs-40.8 +/- 1.6 mV，n=10，P < 0.05）。5 SP（10 mM）和CA（1 nM）也分别抑制Kv7.1+minK电流38.6 +/- 2.3和22.1 +/-1.4%，而不改变沟道激活的电压依赖性。SP，但不是CA，减缓了尾电流衰减的时间过程。6 CA（1 nM）抑制I-Kur（29.2 +/- 5.5%）和I-to 1（16.1 +/- 3.9%）记录在小鼠心室肌细胞和I-K（21.8 +/- 6.9%）。7人心房动作电位的数学模型表明，K+ CA的阻断作用导致动作电位持续时间延长，在正常和心房颤动模拟条件下均是如此。8结果表明，SP和CA都直接阻断hKv1.5、Kv4.3和Kv7.1 + minK通道，CA对这些作用更有效。由于CA的游离血浆峰浓度范围在3和16 nM之间，这些结果表明，在给予治疗剂量的SP后，可以观察到这些人心脏K+通道的阻断。这些心脏K+电流的阻断，以及SP产生的醛固酮促肾上腺皮质激素作用的拮抗作用，可能是治疗室上性心律失常的非常理想的。
1 Both spironolactone (SP) and its main metabolite, canrenoic acid (CA), prolong cardiac action potential duration and decrease the Kv11.1 ( HERG) current. We examined the effects of SP and CA on cardiac hKv1.5, Kv4.3 and Kv7.1+minK channels that generate the human I-Kur, I-to1 and I-Ks, which contribute to the control of human cardiac action potential duration.2 hKv1.5 currents were recorded in stably transfected mouse fibroblasts and Kv4.3 and Kv7.1 + minK in transiently transfected Chinese hamster ovary cells using the whole-cell patch clamp.3 SP (1 mu M) and CA (1 nM) inhibited hKv1.5 currents by 23.2 +/- 3.2 and 18.9 +/- 2.7%, respectively, shifted the midpoint of the activation curve to more negative potentials and delayed the time course of tail deactivation.4 SP (1 mu M) and CA (1 nM) inhibited the total charge crossing the membrane through Kv4.3 channels at +50mV by 27.1 +/- 6.4 and 27.4 +/- 5.7%, respectively, and accelerated the time course of current decay. CA, but not SP, shifted the inactivation curve to more hyperpolarised potentials (V-h-37.0 +/- 1.8 vs -40.8 +/- 1.6 mV, n=10, P < 0.05).5 SP ( 10 mM) and CA (1 nM) also inhibited Kv7.1+minK currents by 38.6 +/- 2.3 and 22.1 +/- 1.4%, respectively, without modifying the voltage dependence of channel activation. SP, but not CA, slowed the time course of tail current decay.6 CA (1 nM) inhibited the I-Kur (29.2 +/- 5.5%) and the I-to1 (16.1 +/- 3.9%) recorded in mouse ventricular myocytes and the I-K (21.8 +/- 6.9%) recorded in guinea-pig ventricular myocytes.7 A mathematical model of human atrial action potentials demonstrated that K+ blocking effects of CA resulted in a lengthening of action potential duration, both in normal and atrial fibrillation simulated conditions.8 The results demonstrated that both SP and CA directly block hKv1.5, Kv4.3 and Kv7.1 + minK channels, CA being more potent for these effects. Since peak free plasma concentrations of CA ranged between 3 and 16 nM, these results indicated that blockade of these human cardiac K+ channels can be observed after administration of therapeutic doses of SP.9 Blockade of these cardiac K+ currents, together with the antagonism of the aldosterone proarrhythmic effects produced by SP, might be highly desirable for the treatment of supraventricular arrhythmias.