Tanaka Hikaru, Hashimoto Norio
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Chiba 274-8510, Japan.
Cardiovasc Drug Rev. 2007 Winter;25(4):342-56. doi: 10.1111/j.1527-3466.2007.00025.x.
Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmia and is associated with increased cardiovascular morbidity and mortality, and the risk of stroke. Although currently available antiarrhythmic drugs are moderately effective in restoring normal sinus rhythm in patients with AF, excessive delay of ventricular repolarization by these agents may be associated with increased risk of proarrhythmia. Therefore, selective blockers of cardiac ion channel(s) that are exclusively present in the atria are highly desirable. NIP-142 is a novel benzopyrane derivative, which blocks potassium, calcium, and sodium channels and shows atrial specific action potential duration prolongation. NIP-142 preferentially blocks the ultrarapid delayed rectifier potassium current (I Kur) and the acetylcholine-activated potassium current (I KACh). Since I Kur and I KACh have been shown to be expressed more abundantly in the atrial than in the ventricular myocardium, the atrial-specific repolarization prolonging effect of NIP-142 is considered to be due to the blockade of these potassium currents. In canine models, NIP-142 was shown to terminate the microreentry type AF induced by vagal nerve stimulation and the macroreentry type atrial flutter induced by an intercaval crush. These effects of NIP-142 have been attributed to the prolongation of atrial effective refractory period (ERP), because this compound prolonged atrial ERP without affecting intraatrial and interatrial conduction times in these models. The ERP prolongation by NIP-142 was greater in the atrium than in the ventricle. NIP-142 also terminated the focal activity type AF induced by aconitine. In addition, NIP-142 reversed the atrial ERP shortening and the loss of rate adaptation induced by short-term rapid atrial pacing in anesthetized dogs. Thus, although clinical trials are required to provide evidence for its efficacy and safety, the novel multiple ion channel blocker, NIP-142, appears to be a useful agent for the treatment of several types of AF with a low risk of proarrhythmic activity.
心房颤动（AF）是最常见的心律失常之一，与心血管疾病发病率和死亡率增加以及中风风险相关。尽管目前可用的抗心律失常药物在恢复AF患者的正常窦性心律方面有一定疗效，但这些药物导致的心室复极过度延迟可能与心律失常风险增加有关。因此，非常需要选择性阻断仅存在于心房的心脏离子通道的药物。NIP-142是一种新型苯并吡喃衍生物，可阻断钾、钙和钠通道，并表现出心房特异性动作电位时程延长。NIP-142优先阻断超快速延迟整流钾电流（I Kur）和乙酰胆碱激活钾电流（I KACh）。由于已证明I Kur和I KACh在心房心肌中的表达比心室心肌中更丰富，因此NIP-142的心房特异性复极延长作用被认为是由于这些钾电流的阻断。在犬模型中，NIP-142被证明可终止由迷走神经刺激诱发的微折返型AF和由腔静脉挤压诱发的大折返型心房扑动。NIP-142的这些作用归因于心房有效不应期（ERP）的延长，因为在这些模型中该化合物延长了心房ERP而不影响心房内和心房间传导时间。NIP-142导致的ERP延长在心房中比在心室中更明显。NIP-142还可终止由乌头碱诱发的局灶性活动型AF。此外，NIP-142可逆转麻醉犬短期快速心房起搏引起的心房ERP缩短和频率适应性丧失。因此，尽管需要进行临床试验以证明其疗效和安全性，但新型多离子通道阻滞剂NIP-142似乎是一种治疗多种类型AF且心律失常活性风险较低 的有用药物。
