KB-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs

Akira Miyata, Douglas P. Zipes, Stephen Hall, Michael Rubart-von der Lohe

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background - To test the hypothesis that Ca2+ influx via Na+/Ca2+ exchange (NCX) underlies atrial fibrillation (AF)-induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca2+-influx mode NCX, to attenuate this effect. Methods and Results - Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean±SEM) 4.4±0.4% (1 mg/kg) to 14.8±2.6% (5 mg/kg; ED50=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacing-induced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9±2.1% after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg · min-1) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86±3.26 nmol/L; n=4 dogs) and declined to 0.56±0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged ≈40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca2+ influx in isolated canine right atrial myocytes by ≈60%, but had no significant effect on NCX-dependent Ca2+ extrusion. Conclusion - NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.

Original languageEnglish
Pages (from-to)1410-1419
Number of pages10
JournalCirculation
Volume106
Issue number11
DOIs
StatePublished - Sep 10 2002

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Atrial Fibrillation
Dogs
Intravenous Infusions
Isoflurane
Pharmaceutical Preparations
Muscle Cells
Canidae
2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate

Keywords

  • Atrium
  • Electrophysiology
  • Fibrillation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

KB-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs. / Miyata, Akira; Zipes, Douglas P.; Hall, Stephen; Rubart-von der Lohe, Michael.

In: Circulation, Vol. 106, No. 11, 10.09.2002, p. 1410-1419.

Research output: Contribution to journalArticle

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abstract = "Background - To test the hypothesis that Ca2+ influx via Na+/Ca2+ exchange (NCX) underlies atrial fibrillation (AF)-induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca2+-influx mode NCX, to attenuate this effect. Methods and Results - Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean±SEM) 4.4±0.4{\%} (1 mg/kg) to 14.8±2.6{\%} (5 mg/kg; ED50=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacing-induced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9±2.1{\%} after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg · min-1) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86±3.26 nmol/L; n=4 dogs) and declined to 0.56±0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged ≈40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca2+ influx in isolated canine right atrial myocytes by ≈60{\%}, but had no significant effect on NCX-dependent Ca2+ extrusion. Conclusion - NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.",
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