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(Circulation. 2002;106:1410.)
© 2002 American Heart Association, Inc.

Basic Science Reports

KB-R7943 Prevents Acute, Atrial Fibrillation–Induced Shortening of Atrial Refractoriness in Anesthetized Dogs

From the Krannert Institute of Cardiology (A.M., D.P.Z., M.R.) and Department of Medicine, Division of Clinical Pharmacology (S.H.), Wishard Memorial Hospital, Indianapolis, Ind.

Correspondence to Michael Rubart, MD, Wells Center for Pediatric Research, Riley Hospital, 702 Barnhill Dr, Indianapolis, IN 46202. E-mail mrubartv{at}iupui.edu

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 · kg^-1 · 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.

Key Words: atrium • fibrillation • electrophysiology

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