Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium

Tomoyuki Matsuda, Kentaro Takeda, Mie Ito, Reiko Yamagishi, Miku Tamura, Hideki Nakamura, Noriko Tsuruoka, Tomoaki Saito, Haruko Masumiya, Takeshi Suzuki, Naoko Iida-Tanaka, Maho Itokawa-Matsuda, Toru Yamashita, Nobutomo Tsuruzoe, Hikaru Tanaka, Koki Shigenobu

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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 G-protein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; IKACh) 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 IKACh, 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 IKACh 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 IKACh 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.

Original languageEnglish
Pages (from-to)33-40
Number of pages8
JournalJournal of Pharmacological Sciences
Volume98
Issue number1
DOIs
Publication statusPublished - 2005 May 1

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Keywords

  • Action potential duration
  • Antiarrhythmic agent
  • NIP-142
  • Refractory period

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Matsuda, T., Takeda, K., Ito, M., Yamagishi, R., Tamura, M., Nakamura, H., Tsuruoka, N., Saito, T., Masumiya, H., Suzuki, T., Iida-Tanaka, N., Itokawa-Matsuda, M., Yamashita, T., Tsuruzoe, N., Tanaka, H., & Shigenobu, K. (2005). Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium. Journal of Pharmacological Sciences, 98(1), 33-40. https://doi.org/10.1254/jphs.FPJ04045X