Blockade by NIP-142, an Antiarrhythmic Agent, of Carbachol-Induced Atrial Action Potential Shortening and GIRK1/4 Channel

Abstract

Abstract. Mechanisms for the atria-specific action potential-prolonging action of NIP-142 ((3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol), a benzopyran compound that terminates experimental atrial arrhythmia, was examined. In isolated guinea-pig atrial tissue, NIP-142 reversed the shortening of action potential duration induced by either carbachol or adenosine. These effects were mimicked by tertiapin, but not by E-4031. NIP-142 concentration-dependently blocked the human G protein-coupled inwardly rectifying potassium channel current (GIRK1 / 4 channel current) expressed in HEK-293 cells with an EC 50 value of 0.64 µM. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC 50 value of 44 µM. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under β-adrenergic stimulation, indicating lack of effect on the muscarinic receptor and Gi protein. These results suggest that NIP-142 directly inhibits the acetylcholine-activated potassium current.

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

“…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). The inhibition of GIRK1/GIRK4 current amplitude in HEK293 cells by 0.1, 1 and 10 μmol/L NIP-142 was 28.9 ± 5.3%, 58.4 ± 6.2% and 76.8 ± 8.4%, respectively (Matsuda et al, 2006). The inhibition was independent from the voltage dependency of the voltage clamp pulse.…”

“…The delayed rectifier current has three components: the rapid component, I Kr , the slow component, I Ks and the ultrarapid component, I Kur . The effects on I Kr , I Ks and I Kur were examined with HEK293 cells expressing the human ether a-go-go (hERG) channel, the human KCNQ1/KCNE1 channel and human K v 1.5 channel, respectively (Matsuda et al, 2001(Matsuda et al, , 2006. NIP-142 concentration-dependently inhibited these three channel currents.…”

“…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).…”

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.…”

“…NIP-142 was shown to inhibit the acetylcholine-activated potassium channel current and prolong the action potential duration in guinea-pig atrial myocardium. 8) Thus, although further investigation is necessary for definitive conclusions, the most likely explanation for the effects of NIP-142 in mouse atria at present is that NIP-142 prolongs the atrial action potential duration through blockade of the transient outward current as well as the acetylcholine-activated potassium current, and produces prolongation of the effective refractory period.…”