nip142 and Atrial-Fibrillation

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.

Topics: Animals; Area Under Curve; Atrial Fibrillation; Benzopyrans; Delayed Rectifier Potassium Channels; Humans; Ion Channels; Membrane Potentials; Models, Biological; Molecular Structure

Effects of NIP-142, a benzopyran compound which terminates experimental atrial arrhythmia, on potassium channel alpha-subunits and mouse atrial repolarization were examined. NIP-142 concentration-dependently blocked the outward current through potassium channel alpha subunits Kv1.5, Kv4.2 and Kv4.3 expressed in Xenopus oocytes. In isolated mouse atrial myocardia, NIP-142 prolonged the action potential duration and effective refractory period, and increased the contractile force. These results suggest that NIP-142 blocks the potassium channels underlying the transient and sustained outward currents, which may contribute to its antiarrhythmic activity.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzopyrans; Dose-Response Relationship, Drug; Heart Atria; Mice; Muscle Contraction; Myocardium; Oocytes; Shaker Superfamily of Potassium Channels; Xenopus

The effects of a new benzopyran derivative, NIP-142, on atrial fibrillation (AF) and flutter (AFL) and on electrophysiological variables were studied in the dog. NIP-142 (3mg/kg) was administered intravenously to pentobarbital-anesthetized beagles during vagally-induced AF and during AFL induced after placement of an intercaval crush. Isolated canine atrial tissues were studied using standard microelectrode technique. NIP-142 terminated AF in 5 of 6 dogs after an increase in fibrillation cycle length (CL) and prevented reinitiation of AF in all 6 dogs. NIP-142 terminated AFL in all 6 dogs without any appreciable change in flutter CL, and prevented reinitiation of AFL in all 6 dogs. NIP-142 prolonged atrial effective refractory periods (11+/-5%, 3+/-3%, 12+/-3%, and 10+/-5% from the baseline value at basic CLs of 150, 200, 300, and 350ms, respectively) without changes in intraatrial conduction time. The prolongation of the atrial effective refractory period was greater in the presence of vagal stimulation. NIP-142 decreased action potential phase-1 notch and increased phase-2 plateau height without making any changes in the action potential duration, although it did reverse carbachol-induced shortening of the action potential duration. In conclusion, NIP-142 is effective in treating AFL and vagally-induced AF by prolonging atrial refractoriness.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Benzopyrans; Disease Models, Animal; Dogs; Vagus Nerve