Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium.
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 G-protein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I(KACh)) expressed in Xenopus oocytes. NIP-142 (10 and 100 microM) 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 microM), 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 possibly explain its previously described antiarrhythmic 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.
Matsuda
Tomoyuki
T
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba 274-8510, Japan.
Takeda
Kentaro
K
Ito
Mie
M
Yamagishi
Reiko
R
Tamura
Miku
M
Nakamura
Hideki
H
Tsuruoka
Noriko
N
Saito
Tomoaki
T
Masumiya
Haruko
H
Suzuki
Takeshi
T
Iida-Tanaka
Naoko
N
Itokawa-Matsuda
Maho
M
Yamashita
Toru
T
Tsuruzoe
Nobutomo
N
Tanaka
Hikaru
H
Shigenobu
Koki
K
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; C427584:NIP142