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.