Atria Selective Prolongation by NIP-142, an Antiarrhythmic Agent, of Refractory Period and Action Potential Duration in Guinea Pig Myocardium

Abstract

Abstract. 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 Gprotein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I KACh ) expressed in Xenopus oocytes. NIP-142 (10 and 100 µM) 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 µM), 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 possiblly 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.

Effect of NIP-142 on Potassium Channel .ALPHA.-Subunits Kv1.5, Kv4.2 and Kv4.3, and Mouse Atrial Repolarization

“…In guinea-pig myocardium, we have shown that the acetylcholine-activated potassium current is present in the atrial myocardium in the absence of muscarinic receptor stimulation, and that NIP-142 prolongs action potential duration and effective refractory period through blockade of this current. 6,8) Such effect was not observed in the ventricle which may explain the atria-selective nature of NIP-142. Also in the case of the mouse atrium, NIP-142, as well as tertiapin, a peptide inhibitor of the acetylcholine-activated potassium channel, prolonged the late repolarization phase (Figs.…”

“…9) Measurement of the effective refractory period was performed by extracellular recording as previously described. 6) Drugs and Chemicals NIP-142 was synthesized by Nissan Chemical Industries (Tokyo, Japan). NIP-142 was added to the bath solution from a stock solution (100 mM) in 0.1 M HCl.…”

Acetylcholine-Activated Potassium Channel as a Novel Target for AF Treatment

“…NIP-142 concentration-dependently prolonged APD only in the atrium. No significant changes in other action potential parameters, such as resting membrane potential, action potential amplitude and maximum rate of rise (Vmax), were observed (Matsuda et al, 2005). The effects of NIP-142 on refractory period and action potential were different from those of conventional class III agents.…”

“…This compound had a slight effect on I K1 : about 40% inhibition was observed with 10 μmol/L NIP-142. The effect of NIP-142 on I KACh was examined in HEK293 cells (Matsuda et al, 2006) and Xenopus oocytes (Matsuda et al, 2005) expressing the GIRK1/GIRK4 channel. Concentration-dependent inhibition of the current was observed in both types of cells: the inhibitory effect was 8-10 times potent than those on IKur in both cells (Table 2).…”

“…At 10 and 100 μmol/L, NIP-142 concentration-dependently prolonged the refractory period in atrium but not in ventricle (Matsuda et al, 2005). The action potential was measured with standard glass microelectrode techniques.…”