Multiple effects of 4-aminopyridine on feline and rabbit sinoatrial node myocytes and multicellular preparations
Multiple effects of 4-aminopyridine on feline and rabbit sinoatrial node myocytes and multicellular preparations
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DOI：
10.1007/s00424-009-0734-3
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发表时间：
2010-02-01
影响因子：
4.5
通讯作者：
Sanchez-Chapula, Jose A.
中科院分区：
文献类型：
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作者：
Arechiga-Figueroa, Ivan A.;Rodriguez-Martinez, Martin;Sanchez-Chapula, Jose A.
4-氨基吡啶（4-AP）通常用于阻断心脏和非心脏组织中的瞬时外向钾电流I-to。在本研究中，我们发现4-AP对兔离体窦房结肌细胞延迟整流钾电流的快速成分I-Kr的抑制作用分别为25% （1 mM）和51% (5 mM)，对猫离体窦房结肌细胞延迟整流钾电流的缓慢成分I-Ks的抑制作用分别为39% （1 mM）和62% （5 mM）。在猫和兔分离的窦房结肌细胞中，4-AP以电压依赖的方式激活毒蕈碱受体，以增加乙酰胆碱激活的钾电流，I-KACh。在非利血平家兔窦房结中央区域的多细胞制剂中，4-AP产生动作电位超调、频率和舒张去极化率的增加。在β -肾上腺素能拮抗剂心得安的存在下，4-AP产生持续时间的显著增加和最大舒张电位的显著降低，并最终停止窦房中枢区域制剂中的自发活动。在利血平化家兔的多细胞制剂中，4-AP产生的效果与在心得安存在下观察到的效果相似。我们得出结论，4-AP抑制多种心脏K+电流，包括I-to， I-Kr和I-Ks，这些活性掩盖了I-KACh的激活。此外，在多细胞制剂中，4-AP从自主神经末梢释放神经递质。当使用4-AP作为“特异性”I-to阻滞剂时，需要考虑这些多重效应。
4-aminopyridine (4-AP) is commonly used to block the transient outward potassium current, I-to, in cardiac and noncardiac tissues. In the present work, we found that 4-AP inhibited the rapid component of the delayed rectifier potassium current, I-Kr, in rabbit-isolated sinoatrial node myocytes by 25% (1 mM) and 51% (5 mM) and inhibited the slow component of the delayed rectifier potassium current, I-Ks, in cat- isolated sinoatrial node myocytes by 39% (1 mM) and 62% (5 mM). In cat- and rabbit-isolated sinoatrial node myocytes, 4-AP activated muscarinic receptors in a voltage-dependent manner to increase the acetylcholine-activated potassium current, I-KACh. In multicellular preparations of the central region of the sinoatrial node from nonreserpinized rabbits, 4-AP produced an increase in action potential overshoot, frequency, and rate of diastolic depolarization. In the presence of the beta-adrenergic antagonist propranolol, 4-AP produced a marked increase in duration and a marked decrease in maximum diastolic potential and eventually, cessation of the spontaneous activity in preparations from the sinoatrial central region. In multicellular preparations from reserpinized rabbits, 4-AP produced similar effects to those observed in the presence of propranolol. We conclude that 4-AP inhibits multiple cardiac K+ currents, including I-to, I-Kr, and I-Ks, and that these activities mask I-KACh activation. In addition, in multicellular preparations, 4-AP produces neurotransmitter release from the autonomic nerve terminals. These multiple effects need to be considered when using 4-AP as a "specific" I-to blocker.