Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium
Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium
复制标题
DOI：
10.1254/jphs.fpj04045x
复制
发表时间：
2005-05-01
影响因子：
3.5
通讯作者：
Shigenobu, K
中科院分区：
文献类型：
--
作者：
Matsuda, T;Takeda, K;Shigenobu, K
NIP-142是一种新型的苯并吡喃化合物，已被证明可以延长犬心房有效不应期并终止实验性心房颤动。在本研究中，我们研究了NIP-142对离体豚鼠心肌和爪蟾卵母细胞中表达的G蛋白偶联内向整流钾通道电流（乙酰胆碱激活钾电流; I-KACh）的影响。NIP-142（10和100 μ M）浓度依赖性地延长不应期和动作电位持续时间在心房，但不是在心室。E-4031和4-氨基吡啶延长左心房和右心室动作电位时程。在0.5和5 Hz之间的刺激频率下观察到NIP-142延长心房动作电位时程。相反，在较高频率下未观察到E-4031的延长。I-KACh阻滞剂Tertiapin延长心房动作电位时程，但不延长心室。NIP-142完全逆转卡巴胆碱引起的心房动作电位时程缩短。NIP-142（1至100 μ M），以及tertiapin（0.1至100 nM），浓度依赖性地阻断I-KAch，在非洲爪蟾卵母细胞中表达; NIP-142的阻断不受膜电压的影响。总之，NIP-142显示通过阻断I-KACh延长心房不应期和动作电位时程，这可能解释了其先前描述的抗心律失常活性。NIP-142具有不同于经典III类抗心律失常药物的药理学性质，例如心房特异性和缺乏反向频率依赖性，因此似乎有希望用于治疗室上性心律失常。
NIP-142 is a novel benzopyran compound that was shown to prolong the atrial effective refractory period and terminate experimental atrial fibrillation in the dog. In the present study, we examined the effects of NIP-142 on isolated guinea pig myocardium and on the G-protein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I-KACh) expressed in Xenopus oocytes. NIP-142 (10 and 100 mu M) concentration-dependently prolonged the refractory period and action potential duration in the atrium but not in the ventricle. E-4031 and 4-aminopyridine prolonged action potential duration in both left atrium and right ventricle. Prolongation by NIP-142 of the atrial action potential duration was observed at stimulation frequencies between 0.5 and 5 Hz. In contrast, the prolongation by E-4031 was not observed at higher frequencies. Tertiapin, a blocker of I-KACh, prolonged action potential duration in the atrium but not in the ventricle. NIP-142 completely reversed the carbachol-induced shortening of atrial action potential duration. NIP-142 (1 to 100 mu M), as well as tertiapin (0.1 to 100 nM), concentration-dependently blocked I-KAch, expressed in Xenopus oocytes; the blockade by NIP-142 was not affected by membrane voltage. In conclusion, NIP-142 was shown to prolong atrial refractory period and action potential duration through blockade of I-KACh which may possibly explain its previously described antiarrhythic activity. NIP-142 has pharmacological properties that are different from classical class III antiarrhythmic agents such as atria specificity and lack of reverse frequency dependence, and thus appears promising for the treatment of supraventricular arrhythmia.