Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: Comparison with class Ic and III Drugs

Wataru Yamamoto, Norio Hashimoto, Junji Matsuura, Taiichi Machida, Yasuhiro Ogino, Tsunefumi Kobayashi, Yoshihiro Yamanaka, Norihisa Ishiwata, Toru Yamashita, Kojiro Tanimoto, Shunichiro Miyoshi, Keiichi Fukuda, Haruaki Nakaya, Satoshi Ogawa

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 μg·kg·min) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 μg·kg·min) and flecainide (0.13 mg·kg·min) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling.

Original languageEnglish
Pages (from-to)421-427
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume63
Issue number5
DOIs
Publication statusPublished - 2014

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Atrial Fibrillation
Canidae
Flecainide
Pharmaceutical Preparations
Atrial Remodeling
Potassium Channel Blockers
Cholinergic Receptors
Dogs
dofetilide

Keywords

  • Antiarrhythmia agents
  • Atrial fibrillation
  • Electrical remodeling

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing : Comparison with class Ic and III Drugs. / Yamamoto, Wataru; Hashimoto, Norio; Matsuura, Junji; Machida, Taiichi; Ogino, Yasuhiro; Kobayashi, Tsunefumi; Yamanaka, Yoshihiro; Ishiwata, Norihisa; Yamashita, Toru; Tanimoto, Kojiro; Miyoshi, Shunichiro; Fukuda, Keiichi; Nakaya, Haruaki; Ogawa, Satoshi.

In: Journal of Cardiovascular Pharmacology, Vol. 63, No. 5, 2014, p. 421-427.

Research output: Contribution to journalArticle

Yamamoto, W, Hashimoto, N, Matsuura, J, Machida, T, Ogino, Y, Kobayashi, T, Yamanaka, Y, Ishiwata, N, Yamashita, T, Tanimoto, K, Miyoshi, S, Fukuda, K, Nakaya, H & Ogawa, S 2014, 'Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: Comparison with class Ic and III Drugs', Journal of Cardiovascular Pharmacology, vol. 63, no. 5, pp. 421-427. https://doi.org/10.1097/FJC.0000000000000065
Yamamoto, Wataru ; Hashimoto, Norio ; Matsuura, Junji ; Machida, Taiichi ; Ogino, Yasuhiro ; Kobayashi, Tsunefumi ; Yamanaka, Yoshihiro ; Ishiwata, Norihisa ; Yamashita, Toru ; Tanimoto, Kojiro ; Miyoshi, Shunichiro ; Fukuda, Keiichi ; Nakaya, Haruaki ; Ogawa, Satoshi. / Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing : Comparison with class Ic and III Drugs. In: Journal of Cardiovascular Pharmacology. 2014 ; Vol. 63, No. 5. pp. 421-427.
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abstract = "The present study examines the effects of NTC-801, a highly selective acetylcholine (ACh) receptor-activated potassium (KACh) channel blocker, on atrial fibrillation (AF) in a canine model with electrical remodeling. An experimental substrate for AF was created in dogs via left atrial (LA) tachypacing (400 bpm, 3-5 weeks). NTC-801, dofetilide, and flecainide were intravenously infused for 15 minutes, and the effects on AF inducibility, atrial effective refractory period (ERP), and atrial conduction velocity were examined. The effect of NTC-801 on AF termination was also evaluated. Atrial ERP was shortened and AF inducibility was increased after LA tachypacing. NTC-801 (0.3-3 μg·kg·min) prolonged atrial ERP irrespective of stimulation frequency and dose-dependently decreased AF inducibility. Dofetilide (5.3 μg·kg·min) and flecainide (0.13 mg·kg·min) did not significantly inhibit AF inducibility and minimally affected atrial ERP. Flecainide decreased atrial conduction velocity, whereas NTC-801 and dofetilide did not. NTC-801 (0.1 mg/kg) converted AF to normal sinus rhythm. In summary, NTC-801 exerted more effective antiarrhythmic effects than dofetilide and flecainide in a canine LA-tachypacing AF model. The antiarrhythmic activity of NTC-801 was probably due to prolonging atrial ERP independently of stimulation frequency. These results suggest that NTC-801 could prevent AF more effectively in the setting of atrial electrical remodeling.",
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